cancer & its treatment

Prepared by :

Dr. Bharat Mishra, Ph.D Associate Professor & Head

Department of Pharmacology

Nirmala College of Pharmacy,

Muvattupuzha.

E.Mail: [email protected]

Dr. Bharat Mishra, Nirmala College of Pharmacy

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CANCER

Chemotherapy Antineoplastic Agents

• The 30 trillion cells that constitute the adult human body grow and differentiate to take on their many specialized functions in a tightly regulated fashion.

• They proliferate only when required, as a result of a delicate balance between growth-promoting and growth-inhibiting mechanisms that are controlled by an intricate network of intra- and extracellular molecules.


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• In stark contrast, cancer cells override these controlling mechanisms and follow their own internal program for timing their reproduction.

• Indeed, cancer cells can grow in an unrestricted manner.

• And over time they can acquire the ability to migrate from their original site, invade nearby tissues, and form tumors (metastases) at distant organs.

• The primary tumor and its metastases become lethal when they invade and disrupt tissues whose function is vital for survival.


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Differences between: cancer and the normal cell

• (1) The cancer cell does not respect usual cellular growth limits; the reason for this is that these cells presumably do not require all the same growth factors that are necessary to cause growth of normal cells.

• (2) Cancer cells often are far less adhesive to one another than are normal cells.

• Therefore, they have a tendency to wander through the tissues, to enter the blood stream, and to be transported all through the body, where they form area for numerous new cancerous growths.


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• (3) Some cancers also produce angiogenic factors that cause many new blood vessels to grow into the cancer, thus supplying the nutrients required for cancer growth.

• Cancer tissue competes with normal tissues for nutrients.

• Because cancer cells continue to proliferate indefinitely, their number multiplying day by day, cancer cells soon demand essentially all the nutrition available to the body or to an essential part of the body.

• As a result, normal tissues gradually suffer nutritive death.


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Cancer

• “One type of neoplasm (tumor), which is an abnormal mass of tissue, the growth of cell exceeds with that of normal tissues became uncontrolled & persists in same excessive manner even after the cessation of the stimuli”.

• Cancer is not one disease but many disorder that share a profound growth dysregulation.

• Neoplasia literally means "new growth."

Dr. Bharat Mishra, Nirmala College of

Pharmacy 10-01-17 9

• Cancer chemotherapy, can be curative in

certain neoplasms as testicular cancer, non-

Hodgkin's lymphoma, Hodgkin's disease, and

choriocarcinoma as well as childhood cancers

such as acute lymphoblastic leukemia,

Burkitt's lymphoma, Wilms‘ tumor, and

embryonal rhabdomyosarcoma.


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• Chemotherapy combined with initial surgery can

increase the cure rate in locally advanced early-

stage breast cancer, esophageal cancer, rectal

cancer, and osteogenic sarcoma.

• All cancers are not curable, so the hope lies in

learning more about its cause & pathogenesis

especially the molecular basis of the cancer.


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• Fundamental to the origin of all neoplasms is loss of responsiveness to normal growth controls.

• There are more than 200 different types of cancer, all of which are characterized by abnormal cellular functioning.

• Normally, our cells undergo mitosis only when necessary and stop when appropriate.

• A cut in the skin, for example, is repaired by mitosis, usually without formation of excess tissue.


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• The new cells fill in the damaged area, and mitosis slows when the cells make contact with surrounding cells.

• This is called contact inhibition, which limits the new tissue to just what is needed.

• A neoplasm is often referred to as a tumor, and the study of tumors is called oncology.


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Cancer

• Two types:

1. Benign tumor: remain localised, can’t spread to

other sites, and it is generally amenable to local

surgical removal; the patient generally survives.

2. Malignant tumor: are collectively referred to as

cancers, the lesion can invade, destroy adjacent

structures and spread to distant sites (metastasize)

to cause death.



• Benign tumors generally do not spread by

invasion or metastasis

• Malignant tumors are capable of spreading

by invasion and metastasis

Malignant versus Benign Tumors


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Benign Tumors

• In general, benign tumors are designated by attaching the suffix -oma to the cell type from which the tumor arises.

• A benign tumor arising in fibrous tissue is a fibroma; a benign cartilaginous tumor is a chondroma.

• Examples of benign tumors are-

• Adenoma: is applied to benign epithelial neoplasms showing gland patterns.

• Papillomas: are benign epithelial neoplasms, growing on any surface, that produce microscopic or macroscopic finger-like fronds.


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• A polyp: is a mass that projects above a mucosal surface, & form a macroscopically visible structure.

• Although this term commonly is used for benign tumors, some malignant tumors also may appear as polyps.

• Cystadenomas: are hollow cystic masses; typically they are seen in the ovary.

• Malignant Tumors

• Malignant neoplasms arising in mesenchymal tissue or its derivatives are called sarcomas.

• A cancer of fibrous tissue origin is a fibrosarcoma, and a malignant neoplasm composed of chondrocytes is a chondrosarcoma.



• Malignant neoplasms of epithelial cell origin are called carcinomas.

• Examples of Carcinomas:

• Squamous cell carcinoma: would denote a cancer in which the tumor cells resemble stratified squamous epithelium.

• Adenocarcinoma: denotes a lesion in which the neoplastic epithelial cells grow in gland patterns.

• Poorly differentiated carcinoma: Sometimes the tumor grows in an undifferentiated pattern.


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• Mixed tumors: In some instances, however, the stem cell may undergo divergent differentiation, creating so-called mixed tumors.

• The best example is mixed tumor of salivary gland origin, also called as Pleomorphic adenoma and Fibroadenoma of the female breast is another common mixed tumor.


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• This benign tumor contains a mixture of proliferated ductal elements (adenoma) embedded in a loose fibrous tissue (fibroma).

• Although only the fibrous component is neoplastic.

• Teratoma: which contains recognizable mature or immature cells of more than one germ-cell layer and sometimes all three (ectoderm, mesoderm, and endoderm).


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• Normally present in the ovary and testis and sometimes abnormally present in embryonic linings.

• When all the component parts are well differentiated, it is a benign (mature) teratoma.

• when less well differentiated, it is an immature, potentially or overtly malignant teratoma.

• The terms lymphoma, mesothelioma, melanoma, and seminoma are used for malignant neoplasms.


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N OM E N C L A T U R E O F T UMO R S


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• Approximately 90-95% of all cancers

are sporadic.

• 5-10% are inherited.

CANCER AND GENETICS


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• Our cells are genetically programmed to have particular life spans and to divide or die.

• One gene is known to act as a brake on cell division; another gene enables cells to live indefinitely, beyond their normal life span, and to keep dividing.

• Any imbalance in the activity of these genes may lead to abnormal cell division.

• Often the malignant cells are carried by the lymph or blood to other organs such as the liver, where secondary tumors develop.



• Cancer is caused in all or almost all instances by mutation or by some other abnormal activation of cellular genes that control cell growth and cell mitosis.

• The abnormal genes are called oncogenes.

• As many as 100 different oncogenes have been discovered.

• Also present in all cells, are, antioncogenes, which suppress the activation of specific oncogenes.



• Therefore, loss of or inactivation of antioncogenes can allow activation of oncogenes that lead to cancer.

• Only a minute fraction of the cells that mutate in the body ever lead to cancer.

• There are several reasons for this.

• First, most mutated cells have less survival capability than normal cells and simply die.

• Second, only a few of the mutated cells that do survive become cancerous.



• Third, potentially cancerous cells are often, if not usually, destroyed by the body’s immune system before they grow into a cancer.

• People, taking immunosuppressant drugs after kidney or heart transplantation, the probability of developing cancer is fivefold.

• Fourth, usually several different activated oncogenes are required simultaneously to cause a cancer.

• For instance, one such gene might promote rapid reproduction of a cell line, but no cancer occurs because there is not a simultaneous mutant gene to form the needed blood vessels.



• Many trillions of new cells are formed each year in humans, Why not, all of us, develop millions or billions of mutant cancerous cells?

• The answer is, the incredible precision with which, DNA replication takes place in each cell before mitosis.

• and also the proofreading process that cuts and repairs any abnormal DNA strand before the mitotic process is allowed to proceed.


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• Yet, despite all these inherited cellular precautions, probably one newly formed cell in every few million still has significant mutant characteristics and forms large number of cancers cells.

• The probability of mutations can be increased manyfold when a person is exposed to following factors:

• Ionizing radiation: such as x-rays, gamma rays, and particle radiation from radioactive substances, and even ultraviolet light can predispose individuals to cancer.


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• Chemical substances(carcinogens): as aniline dye derivatives.

• The carcinogen that currently cause the one quarter of all cancer deaths are those in cigarette smoke.

• Physical irritants: such as continued abrasion of the linings of the intestinal tract by some types of food.

• The damage to the tissues leads to rapid mitotic replacement of the cells.

• The more rapid the mitosis, the greater the chance for mutation.


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• Hereditary tendency:

• Certain types of viruses: can cause some kinds of cancer including leukemia.

• DNA & RNA viruses causes mutations generaly in lab animals.

• Oncogenic RNA viruses all appear to contain a reverse transcriptase enzyme that permits translation of the RNA message of the tumor virus into the DNA code of the infected cell.

• A specific human retrovirus (HTLV-I) has been identified as being the causative agent for a specific type of human T cell leukemia.


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• Oncogenes

• Tumor suppressor genes

• DNA repair genes

Genes playıng role ın cancer

development


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Genes responsible for cancer

cell growth?

Normal

Cancer

Proto-oncogenes Cell growth

and

proliferation Tumor suppressor genes

+

-

Mutated or “activated”

oncogenes Malignant

transformation Loss or mutation of

Tumor suppressor genes

++


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ONCOGENES

• Oncogenes are mutated forms of cellular proto- oncogenes.

• Proto- oncogenes code for cellular proteins which regulate normal cell growth and differentiation.


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Activation mechanisms of proto-oncogenes

proto-oncogene --> oncogene


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Class I: Growth Factors

Class II: Receptors for Growth Factors and Hormones

Class III: Intracellular Signal Transducers

Class IV: Nuclear Transcription Factors

Class V: Cell-Cycle Control Proteins

Five types of proteins encoded by proto-

oncogenes participate in control of cell growth:


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4. Nuclear

Proteins:

Transcription

Factors

5. Cell Growth

Genes

3. Cytoplasmic

Signal Transduction

Proteins

1. Secreted

Growth Factors

2. Growth Factor Receptors

Functions of Cellular Proto-Oncogenes


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A general signalling

pathway


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Tumor suppressor genes

• Another class of genes, which may be deleted or damaged, resulting neoplastic changes.

• A single gene in this class, the p53 gene, has been shown to have mutated from a tumor suppressor gene to an oncogene in a high percentage of cases of several human tumors, including liver, breast, colon, lung, cervix, bladder, prostate, and skin.


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p53 • Phosphyorylated p53 activates

transcription of p21 gene • p21 Cdk inhibitor (binds Cdk-

cyclin complex --> inhibits kinase activity)

• Cell cycle arrested to allow DNA to be repaired • If damage cannot be repaired --> cell death (apoptosis) • Disruption/deletion of p53 gene • Inactivation of p53 protein --> uncorrected DNA damage --> uncontrolled cell proliferation --

> cancer

Ataxia telangictasia mutated


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Gene Mutation: Chromosomal changes in the genome of

cancer cells

Terminal

Deletion

Ring

Chromosome

Robertsonian

Translocation

Deletion Reciprocal

translocation

Isochromosomes Insertion Inversion

Duplication


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Nucleotide changes in the genome of cancer cells:

Nucleotide Deletions

Nucleotide Insertions

Nucleotide Substitutions

http://www.tokyo-med.ac.jp/genet/cai-e.htm Dr. Bharat Mishra, Nirmala College of


Growth rate

• Most benign tumors grow slowly, and most cancers grow much faster, eventually metastasizing and causing death.

• some benign tumors grow more rapidly than some cancers.

• For example, the rate of growth of leiomyomas (benign smooth muscle tumors) of the uterus is influenced by the circulating levels of estrogens.

• They may increase rapidly in size during pregnancy and cease growing or atrophy after menopause.


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Tumor enlargement

• Tumors cannot enlarge beyond 1 to 2 mm in diameter or thickness unless they are vascularized.

• Then oxygen and nutrients can diffuse from blood vessels.

• The tumor fails to enlarge without vascularization because hypoxia induces, apoptosis by activation of TP53 .

• Neovascularization has a dual effect on tumor growth:

Perfusion supplies nutrients and oxygen,


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And newly formed endothelial cells stimulate the growth of adjacent tumor cells by secreting polypeptides, such as insulin-like growth factors, PDGF, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interleukin (IL)-1.

• Angiogenesis is required not only for continued tumor growth but also for metastasis.

• Tumor-associated angiogenic factors may be produced by tumor cells or may be derived from inflammatory cells e.g are vascular endothelial growth factor (VEGF) and basic fibroblast growth factor.


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• Tumor cells not only produce angiogenic factors but also induce antiangiogenesis molecules.

• Emerging pattern is that, tumor growth is controlled by the balance between angiogenic factors and factors that inhibit angiogenesis.

• Antiangiogenesis factors, such as thrombospondin-1, may be produced by the tumor cells themselves, or their production may be induced by tumor cells.


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• Hypoxia within the growing tumor favors angiogenesis by release of hypoxia-inducible factor-1 (HIF-1).

• HIF-1 controls transcription of VEGF.

• The transcription of VEGF also is under the control of RAS oncogene, and RAS activation up-regulates the production of VEGF.


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• Proteases are also involved in regulating the balance between angiogenic and antiangiogenic factors by releaseing basic fibroblast growth factor.

• Because of the crucial role of angiogenesis in tumor growth, much interest is focused on antiangiogenesis therapy.

• Results of ongoing clinical trials with several angiogenesis inhibitors seem promising, and more are awaited.


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Metastasis

• The term metastasis explains the development of secondary implants (metastases) discontinuous with the primary tumor.

• Malignant neoplasms spread by one of three pathways:

• (1) seeding within body cavities,

• (2) lymphatic spread,

• (3) hematogenous spread.



1-Seeding of cancers

• Occurs when neoplasms invade a natural body cavity.

• Carcinoma of the colon may penetrate the wall of the gut and reimplant at distant sites in the peritoneal cavity.

• A similar sequence may occur with lung cancers in the pleural cavities.


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2-Lymphatic spread:

• Is more typical of carcinomas.

• The pattern of lymph node involvement depends principally on the site of the primary neoplasm and the natural lymphatic pathways of drainage of the site.

• Lung carcinomas arising in the respiratory passages metastasize first to the regional bronchial lymph nodes, then to the tracheobronchial and hilar nodes.


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3- Hematogenous spread:

• Is the most feared consequence of a cancer.

• It is the favored pathway for sarcomas, but carcinomas use it as well.

• As might be expected, arteries are penetrated less readily than are veins.

• The liver and lungs are the most frequently involved secondary sites in such hematogenous dissemination.


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CANCER THERAPY

• Can be performed by-

• 1- Chemotherapy

• 2-Radiotherapy

• 3-Surgery

• 4-Biotherapy


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Biotherapy

• Can be effective against clinically apparent, even bulky cancer.

• The term biotherapy encompasses the therapeutic use of any biological substances.

• For the agents used in biotherapy the name given is “Biological Response Modifiers (BRM)”

• These are the agents and approaches whose mechanism of action involves the individuals own biological responses.


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• BRM works through the diverse mechanisms as-

• (a) Augment the host’s defenses through the administration of cells, natural biologicals, or the synthetic derivatives thereof as effectors or mediators (direct or indirect) of an antitumor response;

• (b) Increase the individual’s antitumor responses through augmentation or restoration of effector mechanisms, or decrease a component of the host’s reaction that is deleterious;


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• (c) Augment the individual’s responses using modified tumor cells or vaccines to stimulate a greater response, or increase tumor cell sensitivity to an existing bio logical response;

• (d) Decrease transformation and/or increase differentiation or maturation of tumor cells;

• (e) Interfere with growth-promoting factors and angiogenesis inducing factors produced by tumor cells;


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• (f) Decrease or arrest the tendency of tumor cells to metastasize to other sites;

• (g) Increase the ability of the patient to tolerate damage by cytotoxic modalities of cancer treatment; and/or,

• (h) use biological molecules to target and bind to cancer cells and induce more effective cytostatic or cytocidial antitumor activity.


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Biologicals and Biological Response Modifiers

1: IMMUNOMODULATING AGENTS

• Alkyl lysophospholipids (ALP)

• Azimexon

• BCG

• Bestatin

• Brucella abortus

• Cornyebacterium parvum

• Cimetidine

• Sodium diethyldithiocarbamate (DTC)

• Endotoxin

• Glucan

• ‘Immune’ RNAs

• Krestin

• Lentinan

• T-cell growth factors (‘TCGF’ – interleukin 2 [IL-2

• Levamisole

• Muramyldipeptide (MDP), tripeptide (MTP)

• Maleic anhydride-divinyl ether (MVE-2)

• Mixed bacterial vaccines (MBV)

• Nocardia rubra cell wall skeletons (CWS)

• Picibanil (OK432)

• Prostaglandin inhibitors (aspirin, indomethacin)

• Thiobendazole

• Tuftsin


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2: Interferons and interferon inducers

• Interferons (α, β, γ)

• Poly IC-LC

• Poly A-U

• GE-132

• Brucella abortus

• Tilorone

• Viruses

• Pyrimidinones

3: Thymosins

• Thymosin alpha-1

• Thymosin fraction 5

• Other thymic factors

4: Antigens

• Tumor-associated antigens

• Molecular vaccines

• Cell-engineered cellular vaccines

5: Effector cells

• Macrophages

• NK cells

• Cytotoxic T cells

• LAK cells

• T helper cells


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5: Lymphokines, cytokines, growth/maturation factors:

• Antigrowth factors

• Chalones

• Colony-stimulating factors (CSF)

• Growth factors (transforming growth factor, TGF)

• Lymphocyte activation factor (LAF-interleukin 1 [IL-1])

• Lymphotoxins (TNF, α, β, LT)

• Macrophage activation factors (MAF)

• Macrophage chemotactic factor

• Macrophage cytotoxic factor (MCF)

• Macrophage growth factor (MGF)

• Migration inhibitory factor (MIF)

• Maturation factors

• Interleukin 3–18, etc.

• Thymocyte mitogenic factor (TMF)

• Transfer factor

• Transforming growth factor (TFR, α, β)

6: Miscellaneous approaches:

• Allogeneic immunization

• Liposome-encapsulated biologicals

• Bone-marrow transplantation and reconstitution

• Plasmapheresis and ex vivo treatments (activation columns, immunoabsorbents, and ultrafi ltration)

• Virus infection of cells (oncolysates)


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Chemotherapy

• An understanding of cell-cycle kinetics is essential for the proper use of antineoplastic agents.


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The Cell Cycle

• Proliferating cells progress through a series of checkpoints and defined phases called the cell cycle.

• The cell cycle consists of-

• Presynthetic growth phase 1, or G1

• DNA-synthetic phase, or S

• Premitotic growth phase 2, or G2

• Mitotic phase, or M.

• Resting cells (cells that are not preparing for cell division) are said to be in a subphase of G1 ie. G0.


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Cell cycle


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• Cyclins proteins control the Entry and progression of cells through the cell cycle.

• Cyclins accomplish their regulatory functions by activating the constitutively synthesized proteins called cyclin-dependent kinases (CDKs), and CDKs inhibited by proteins such as p16.

• Different combinations of cyclins and CDKs are associated with each of the important transitions in the cell cycle.


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• A specific example involves CDK1, which controls the critical transition from G2 to M.


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• After cell division, cyclin B is degraded, until there is a new growth stimulus and synthesis of new cyclins, the cells do not undergo further mitosis.

• The cyclin-CDK complexes are also regulated by the binding of CDK inhibitors.

• These are particularly important in regulating cell cycle checkpoints (G1 → S and G2 → M).

• Points at which the cell checks whether its DNA is sufficiently replicated and all mistakes repaired before progressing.

• Failure to adequately monitor the accuracy of DNA replication leads to the accumulation of mutations and possible malignant transformation.



• As an example, when DNA is damaged (e.g., by ultraviolet irradiation), the tumor suppressor protein TP53 is stabilized and induces the transcription of CDKN1A, a CDK inhibitor.

• This arrests the cells in G1 or G2 until the DNA can be repaired; at that point, the TP53 levels fall, CDKN1A diminishes, and the cells can proceed through the checkpoint.

• If the DNA damage is too extensive, TP53 will initiate a cascade of events to convince the cell to commit suicide.


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• Many of the most effective cytotoxic agents act by damaging DNA.

• Their toxicity is greater during the S, or DNA synthetic, phase of the cell cycle, while others, such as the vinca alkaloids and taxanes, block the formation of a functional mitotic spindle in M phase.

• Conversely, slowly growing tumors with a small growth fraction (for example, carcinomas of the colon or lung cancer) often are less responsive to cycle-specific drugs.


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• Anticancer agents have variable pharmacokinetics and toxicity in individual patients.

• The causes of this variability are not always clear and often may be related to interindividual differences in drug metabolism, drug interactions, or bone marrow reserves.


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Aim of treatment

• In malignant diseases, drugs are used with the aim of:

1. Cure or prolonged remission:

• Chemotherapy is the primary treatment modality that can achieve cure or prolonged remission in:

• Acute leukemias

• Wilm's tumour g

• Ewing's sarcoma

• Retinoblastoma

• Rhabdomyosarcoma

• Seminoma , Mycosis fungoides,Choriocarcinoma ,

• Hodgkin's disease ,Lymphosarcoma

• Burkitt's lymphoma, Testicular teratomas

In childrens


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2. Palliation:

• Shrinkage of evident tumour, alleviation of symptoms and life is prolonged by chemotherapy in:

• Breast cancer, Chronic lymphatic leukemia ,Ovarian carcinoma, Chronic myeloid leukemia, Endometrial carcinoma, Non-Hodgkin lymphomas, Myeloma Head and neck cancers, Prostatic carcinoma Lung (small cell) cancer.

• Many other malignant tumours are less sensitive to drugs-life may or may not be prolonged by chemotherapy are:


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• Colorectal carcinoma, Malignant melanomas

• Carcinoma pancreas, Bronchogenic carcinoma

• Carcinoma stomach (non small cell)

• Carcinoma esophagus, Hepatoma

• Renal carcinoma Sarcoma

3. Adjuvant chemotherapy

• Drugs are used to mop up any residual malignant cells (micro metastases) after surgery or radiotherapy.

• This is routinely employed now.


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CLASSIFICATION OF ANTICANCER DRUGS

A. Drugs acting directly on cells (Cytotoxic drugs)

1. Alkylating agents 2. Anti metabolites

a. Nitrogen mustards : •Mechlorethamine (Mustine HCl) •Cyclophosphamide •Ifosfamide, Chlorambucil, Melphalan

a. Purine antagonist • 6-Mercaptopurine (6-MP), Pentostatin • 6-Thioguanine (6-TG), • Azathioprine, Fludarabine, cladribine

b. Ethylenimine & methylamine: •Thio-TEPA, Altretamine

b. Folate antagonist • Methotrexate (Mtx), Pemetrexed

c. Alkyl sulfonate : •Busulfan d. Methylhydrazine derivative: •Procarbazine

c. Pyrimidine antagonist • 5-Fluorouracil (5-FU), • Cytarabine (cytosine arabinoside) •Capecitabine, Gemcitabine

e. Nitrosoureas: •Carmustine (BCNU) •Lomustine (CCNU) ,streptozotocin

3.Microtubule Inhibitors: a.Vinca alkaloids • Vincristine (Oncovin), • Vinblastine , vinorelbine

f. Triazine •Dacarbazine (DTIC), temozolomide •G. Platinum coordination complexes: •Cisplatin, carboplatin,oxaliplatin

4. Microtubule Inhibitors: b.Taxanes • Paclitaxel, • Docetaxel


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5. Epipodophyllo toxin: • Etoposide, Teniposide

3. Selective estrogen receptor modulators: •Tamoxifen, Toremifene

6. Camptothecin analogues: • Topotecan, Irinotecan

4. Selective estrogen receptor down regulators :

•Fulvestrant

7. Antibiotics: Actinomycin D, (Dactinomycin) Doxorubicin , Daunorubicin (Rubidomycin) Mitoxantrone, Bleomycins, Mitomycin C

5. Aromatase inhibitors •Letrozole, •Anastrozole, •Exemestane

8. Miscellaneous : Hydroxyurea, L-Asparaginase, Imatinib,

Tretinoin, arsenic trioxide, Gefitinib, erlotinib, Bortezomib, Interferon-alfa, interleukin 2

6. Antiandrogen • Flutamide, • Bicalutamide 7. Androgens:Testosterone propionate,

fluoxymesterone

B. DRUGS ALTERING HORMONAL MILIEU 8. 5-α reductase inhibitor • Finasteride, Dutasteride

1. Glucocorticoids : • Prednisolone and others

9. GnRH analogues •Nafarelin, Triptorelin, Leuprolide

2. Estrogens : • Fosfestrol, Ethinylestradiol ,

Diethylstilbestrol

10. Progestins • Hydroxyprogesterone acetate, megestrol

acetate, Hydroxyprogesterone caproate Dr. Bharat Mishra, Nirmala College of Pharmacy

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Cell cycle effects of anticancer drugs


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TOXICITY OF CYTOTOXIC DRUGS

Profound effect on rapidly multiplying cells,

because the target of action are the nucleic acids and their precursors; and,

rapid nucleic acid synthesis occurs during cell division.

Many cancers (especially large solid tumours) have a lower growth fraction than normal bone marrow, epithelial linings, reticuloendothelial (RE) system and gonads.

So these tissues are particularly affected.


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1. Bone marrow

• Depression of bone marrow results in granulocytopenia, agranulocytosis, thrombocytopenia, aplastic anaemia.

• Infections and bleeding are the usual complications.


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2. Lymphoreticular tissue

Lymphocytopenia and inhibition of lymphocyte function,

results in suppression of cell mediated as well as humoral immunity.

susceptibility to all infections is increased.

Particularly the opportunistic infections.

Examples as, fungi (Candida, Pneumocystis jiroveci & others), viruses (Herpes zoster, cytomegalo virus), and Toxoplasma.


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3. Oral cavity

Because of high epithelial cell turnover.

Gums and oral mucosa are regularly subjected to minor trauma, and breaches are common during chewing.

oral infections.

Thrombocytopenia may cause bleeding gums.

Xerostomia due to the drug may cause rapid progression of dental caries.


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4. GIT

• Diarrhoea, shedding of mucosa, haemorrhages occur due to decrease in the rate of renewal of the mucous lining.

• Nausea and vomiting, due to direct stimulation of CTZ as well as generation of emetic impulses from the upper g .i. t.


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5. Skin

Alopecia occurs due to damage to the cells in hair follicles.

Dermatitis is another complication.

• 6. Gonads

Inhibition of gonadal cells causes oligozoospermia and impotence in males;

inhibition of ovulation and amenorrhoea are common in females.

Damage to the germinal cells may result in mutagenesis.


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• 7. Foetus

profoundly damage the developing foetus abortion, foetal death, teratogenesis.

• 8. Carcinogenicity

Secondary cancers, especially leukaemias, lymphomas and histocytic tumours.

due to depression of cell mediated and humoral blocking factors against neoplasia.


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9. Hyperuricaemia

This is secondary to massive cell destruction

(uric acid is a product of purine metabolism).

Gout and urate stones in the urinary tract

may develop.


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DRUG TREATMENT


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General mechanisms for drugs acting on cell growth components dTMP = deoxythymidine monophosphate [slide no.77 &78]


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PALA =N-phosphonoacetyl-L-aspartate; TMP = thymidine monophosphate.


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ALKYLATING AGENTS

• The major clinically useful alkylating agents

have a structure containing a

chloroethylamine, ethyleneimine, or

nitrosourea moiety.


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Mechanism of action

• The general mechanism of action of these

drugs involves intramolecular cyclization to

form an ethyleneimonium ion that may

directly or through formation of a carbonium

ion transfer an alkyl group to a cellular

constituent.


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• N3 of cytosine, and O6 of guanine, as well as phosphate atoms and proteins associated with DNA.

• The major site of alkylation within DNA is the N7 position of guanine,

• however, other bases are also alkylated to lesser degrees, including N1 and N3 of adenine,


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• The latter effect leads to DNA strand breakage through scission of the sugar-phosphate backbone of DNA.

• These interactions can occur on a single strand or on both strands of DNA through cross-linking.

• Alkylation of guanine can result in miscoding through abnormal base pairing with thymine or in de-purination by excision of guanine residues.



Intramolecular cyclization

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Ethyleneimonium ion Carbonium Ion

Directly

Alkyl group

Transfer to DNA

N7 position of guanine

N1 and N3 of adenine, N3 of cytosine

O6 of guanine

Phosphate atoms and proteins associated with DNA.

Abnormal base pairing with thymine

de-purination by excision of guanine residues.

Miscoding

Scission of the sugar-phosphate backbone of DNA

DNA strand breakage

• Thus, Although alkylation can occur in both

cycling and resting cells, so the alkylating

agents are not cell cycle-specific.

• Cells are most susceptible to alkylation in late

G1 and S phases of the cell cycle and express

block in G2.

10-01-17 Dr. Bharat Mishra, Nirmala College of

Pharmacy 100

Mechanisms of Resistance to Alkylating Agents

• Resistance develops rapidly as a single agent.

• Specific biochemical changes implicated as:

• Decreased permeation of actively transported drugs (mechlorethamine and melphalan);

• Increased intracellular concentrations of nucleophilic substances, principally thiols such as glutathione, which can conjugate with and detoxify electrophilic intermediates;


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• Increased activity of DNA repair pathways, which may differ for the various alkylating agents.

• Thus, increased activity of the complex nucleotide excision repair (NER) pathway seems to correlate with resistance.

• Increased rates of metabolism of the activated forms of cyclophosphamide and ifosfamide to their inactive keto and carboxy metabolites by aldehyde dehydrogenase.


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Toxicities of Alkylating Agents

• Bone Marrow Toxicity:

• Most cause dose-limiting toxicity to bone marrow elements.

• Most alkylating agents, including nitrogen mustard, melphalan, chlorambucil, cyclophosphamide, and ifosfamide, cause acute myelosuppression.

• Busulfan suppresses all blood elements, particularly stem cells, and may produce a prolonged and cumulative myelosuppression lasting months or even years.


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• Carmustine and other chloroethyl nitrosoureas cause delayed and prolonged suppression of both platelets and granulocytes.

• Both cellular and humoral immunity are suppressed by alkylating agents, which have been used to treat various autoimmune diseases.

• Immunosuppression is reversible.


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• Mucosal Toxicity:

• Highly toxic to dividing mucosal cells, leading

to oral mucosal ulceration and intestinal

denudation.

• Cyclophosphamide, melphalan, and thiotepa

have the advantage of causing less mucosal

damage than the other agents.


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• Neurotoxicity

• CNS toxicity is manifest in the form of nausea

and vomiting, particularly after intravenous

administration of nitrogen mustard.

• Ifosfamide is the most neurotoxic of this class

of agents, producing altered mental status,

coma, generalized seizures, and cerebellar

ataxia.


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• Other Organ Toxicities

• May occur after prolonged or high-dose use; can appear after months or years, and may be irreversible and even lethal.

• All alkylating agents have caused pulmonary fibrosis, usually several months after treatment.

• The nitrosoureas and ifosfamide, after multiple cycles of therapy, may lead to renal failure.


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• Cyclophosphamide and ifosfamide release a

nephrotoxic and urotoxic metabolite, acrolein,

which causes a severe hemorrhagic cystitis.

• Cystitis a side effect that in high-dose regimens

can be prevented by coadministration of 2-

mercaptoethanesulfonate (mesna or MESNEX),

which conjugates acrolein in urine.


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• Ifosfamide in high doses for transplant causes

a chronic, and often irreversible, renal toxicity.

• Proximal, and less commonly distal tubules

may be affected, with difficulties in Ca2+ and

Mg2+ reabsorption, glycosuria, and renal

tubular acidosis.


Pharmacy 109

• All alkylating agents have toxic effects on the

male and female reproductive systems,

• causing an often permanent amenorrhea,

particularly in premenopausal women, and an

irreversible azoospermia in men.


Pharmacy 110

• Leukemogenesis:

• These agents are highly leukemogenic.

• Acute nonlymphocytic leukemia, often associated

with partial or total deletions of chromosome 5

or 7.

• Very common in Melphalan, the nitrosoureas,

and the methylating agent procarbazine .

• less common with cyclophosphamide.


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Cyclophosphamide

• A nitrogen mustard,

• Cytotoxic action is similar to that of other alkylating agents.

• Therapeutic Uses

• Cyclophosphamide is administered orally or intravenously.


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• As a single agent & adjuvant therapy, a daily oral dose of 100 mg for 14 days has been recommended for breast cancer, and for patients with lymphomas and chronic lymphocytic leukemia.

• A higher dosage of 500 mg intravenously every 2 to 4 weeks in combination with other drugs often is employed in the treatment of breast cancer and lymphomas.


Pharmacy 113

• Common: Gastrointestinal ulceration, cystitis, and,

• less common: pulmonary, renal, hepatic, and cardiac toxicities (a hemorrhagic myocardial necrosis) may occur after high-dose therapy with total doses above 200 mg/kg.

• It is an essential component of many effective drug combinations for non-Hodgkin's lymphomas, ovarian cancers, and solid tumors in children.


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• Complete remissions and presumed cures have been reported when Cyclophosphamide was given as a single agent for Burkitt's lymphoma.

• It frequently used in combination with methotrexate (or doxorubicin) and fluorouracil as adjuvant therapy after surgery for carcinoma of the breast.

• Because of its potent immunosuppressive properties, it has been used to prevent organ rejection after transplantation.


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Nitrosoureas

• The nitrosoureas appear to function by cross-

linking through alkylation of DNA.

• More effective against plateau phase cells

than exponentially growing cells,

• Slow effect in cycling cell progression in the

DNA synthetic phase.


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• Because of its ability to cross the blood–brain

barrier, carmustine is used with procarbazine

in the treatment of malignant gliomas.

• Nausea and vomiting, Leukopenia,

thrombocytopenia, and rarely hepatitis are

adverse effects of Lomustine and carmustine.


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Pharmacokinetics

• Highly lipid-soluble and cross the blood-brain

barrier, useful in the treatment of brain

tumors.

• After oral administration of lomustine, peak

plasma levels of metabolites appear within 1–

4 hours.

• Elimination through Urinary excretion.


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• One naturally occurring sugar-containing

nitrosourea, streptozocin, is interesting

because it has minimal bone marrow toxicity.

• This agent has activity in the treatment of

insulin-secreting islet cell carcinoma of the

pancreas.


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Toxicity of STZ

• Nausea is frequent.

• Mild, reversible renal or hepatic toxicity.

• In less than 10% of patients, renal toxicity may be

cumulative with each dose and may be fatal.

• Should be avoided with other nephrotoxic drugs.

• Hematological toxicity—anemia, leukopenia, or

thrombocytopenia—occurs in 20% of patients.


Pharmacy 10-01-17 120

Methylhydrazines

Procarbazine

• An orally active drug,

• it is used in combination regimens for Hodgkin’s and

non-Hodgkin’s lymphoma as well as brain tumors.

• it inhibits DNA, RNA, and protein biosynthesis;

• prolongs interphase;

• and produces chromosome breaks.


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• Oxidative metabolism of this drug by

microsomal enzymes generates azopro-

carbazine and H2O2 , which may be

responsible for DNA strand scission.


Pharmacy 122

• A variety of other drug metabolites are formed that may be

cytotoxic.

• One metabolite is a weak MAO inhibitor,

• and adverse events can occur when-

• Procarbazine is given with other MAO inhibitors, with

sympathomimetics, tricyclic antidepressants, antihistamines, CNS

depressants, antidiabetic agents, alcohol, and tyramine-containing

foods.

• There is an increased risk of secondary cancers.

• it is more carcinogenic than other alkylating agents.


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Triazenes

Dacarbazine (DTIC)

• Dacarbazine is a synthetic compound.

• Forms metabolite which is monomethyl derivative.

• This metabolite spontaneously decomposes to

diazomethane, which generates a methyl carbonium

ion that is cytotoxic .

• It is administered parenterally .


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• Used in the treatment of malignant

melanoma, Hodgkin’s lymphoma, soft tissue

sarcomas, and neuroblastoma.

• Main dose-limiting toxicity is

myelosuppression, but nausea and vomiting

can be severe in some cases.

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125

Alkyl Sulfonates

Busulfan Pharmacological and Cytotoxic Actions

• It produces little effect on lymphoid tissue

and GIT.

• In high-dose regimens, pulmonary fibrosis, gastrointestinal mucosal damage, and veno-occlusive disease of the liver become important.


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Therapeutic Uses

• Chronic myeloid leukemia, the initial oral dose of

busulfan varies with the total leukocyte count and

the severity of the disease.

• Daily doses from 2 to 8 mg for adults (60 g/kg for

children) are used to initiate therapy.

• High doses of busulfan with high doses of

cyclophosphamide, used to prepare leukemia

patients for bone marrow transplantation.


Pharmacy 127

• Anticonvulsants must be used concomitantly to

protect against acute CNS toxicities, including

tonic-clonic seizures, which may occur several

hours after each dose.

• Busulfan induces the metabolism of Phenytoin.

• So lorazepam are recommended as an alternative

to phenytoin.


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Clinical Toxicity

• Myelosuppressive properties, and prolonged

thrombocytopenia .

• Occasional nausea, vomiting, and diarrhea.

• Long-term use leads to impotence, sterility,

amenorrhea, and fetal malformation.

• Rarely, asthenia and hypotension, a syndrome

resembling Addison's disease.


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• High-dose busulfan causes veno-occlusive

disease of the liver, seizures, hemorrhagic

cystitis, permanent alopecia, and cataracts.

• The coincidence of veno-occlusive disease and

hepatotoxicity is increased by its

coadministration imidazoles and

metronidazole.


Pharmacy 130

Antimetabolites

• Structurally related to normal compounds that exist within the cell.

• They generally interfere with the availability of normal purine or pyrimidine nucleotide precursors,

• either by inhibiting their synthesis

• or by competing with them in DNA or RNA synthesis.

• Their maximal cytotoxic effects are in S-phase therefore, cell-cycle specific.


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1. Folate antagonist Methotrexate (Mtx)

• The vitamin, folic acid plays a central role in a variety of metabolic reactions involving the transfer of one-carbon units and is essential for cell replication.

• Methotrexate (MTX) is structurally related to folic acid and acts as an antagonist of that vitamin by inhibiting dihydrofolate reductase 2 (DHFR) [the enzyme that converts folic acid to its active, coenzyme form, tetrahydrofolic acid (FH4)].


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Mechanism of action:


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Mechanism of action of methotrexate and the effect of administration of leucovorin. FH2 =dihydrofolate; FH4 = tetrahydrofolate; dTMP = deoxythymidine monophosphate; dUMP = deoxyuridine mono phosphate.

Folic acid is obtained from dietary sources or from that produced by intestinal flora.

It undergoes reduction to the tetrahydrofolate (FH4) form catalyzed by intracellular nicotinamide-adenine dinucleotide

MTX has an unusually strong affinity for DHFR and effectively inhibits the enzyme.

(FH4) : imprtant as carbon carrier for enzymatic processes involved in synthesis of thymidylate, purine nucleotides, and the amino acids serine and methionine.

Thereby interferes with the formation of DNA, RNA, and key cellular proteins .

The inhibition of DHFR can only be reversed by a 1000-fold excess of the natural substrate, dihydrofolate , or by administration of leucovorin, which bypasses the blocked enzyme and replenishes the folate pool.


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Enzymatic reactions that use folates. Section 1 shows the vitamin B 12 -dependent reaction that allows most dietary folates to enter the

tetrahydrofolate cofactor pool. Section 2 shows the dTMP cycle. Section 3 shows the pathway by which folic acid enters the tetrahydrofolate cofactor pool.


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• Folate Di hydrofolate Tetra hydrofolate DHFR DHFR

Methionine Glycine Serine Initiator tRNA

Purine Thymidine

RNA DNA

Proteins

DNA

By donating carbon atom


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• MTX has an unusually strong affinity for DHFR and effectively inhibits the enzyme.

• Intracellular formation of polyglutamate metabolites, with the addition of up to 5–7 glutamate residues, is critically important for the therapeutic action of MTX.

• This process is catalyzed by the enzyme folylpolyglutamate synthase (FPGS).

FPGS

• Glutamate residues Polyglutamate metabolites


Pharmacy 10-01-17 137

• MTX polyglutamates are selectively retained

within cancer cells, and they display increased

inhibitory effects on enzymes involved in de

novo purine nucleotide and thymidylate

biosynthesis, making them important

determinants of MTX’s cytotoxic action.


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Resistance:

• Nonproliferating cells are resistant to MTX, probably because of a relative lack of DHFR, thymidylate synthase, and/or the glutamylating enzyme.

• Decreased levels of the MTX polyglutamate may be due to its decreased formation or increased breakdown.

• Resistance in neoplastic cells can be due to amplification (production of additional copies) of the gene that codes for DHFR, resulting in increased levels of this enzyme.


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• The enzyme affinity for MTX may also be diminished.

• Resistance can also occur from a reduced influx of MTX, apparently caused by a change in the carrier-mediated transport responsible for pumping the drug into the cell.


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Therapeutic uses

• Against acute lymphocytic leukemia, choriocarcinoma,

Burkitt's lymphoma in children, breast cancer, and head

and neck carcinomas.

• In addition, low-dose MTX is effective as a single agent

against certain inflammatory diseases, such as severe

psoriasis and rheumatoid arthritis as well as Crohn's

disease.

• All patients receiving MTX require close monitoring for

possible toxic effects.


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Doses

• Methotrexate is apparently curative in choriocarcinoma: 15-30 mg/ day for 5 days orally or 20-40mg i.v. twice weekly.

• It is also useful in other malignancies, rheumatoid arthritis, psoriasis and as immunosuppressant.

• Marketed preprations: NEOTREXATE 2.5 rng tab, 50 rng/2 rnl inj; BIOTREXATE 2.5 rng tab, 5, 15, 50 rng/vial inj.


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Adverse effects:

• Commonly observed toxicities:

• Nausea, vomiting, and diarrhea, the most frequent toxicities occur in tissues that are constantly renewing.

• Thus, MTX causes stomatitis, myelosuppression, rash, urticaria, and alopecia.

• Some of these adverse effects can be prevented or reversed by administering leucovorin, which is taken up more readily by normal cells than by tumor cells.


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• Doses of leucovorin must be kept minimal to avoid possible interference with the antitumor action of MTX.

• B. Renal damage: Although uncommon during conventional therapy.

• Renal damage is a complication of high-dose MTX and its 7-OH metabolite, which can precipitate in the tubules.

• Alkalinization of the urine and hydration help to prevent this problem.


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• C. Hepatic function:

• Hepatic function should be monitored.

• Long-term use of MTX may lead to cirrhosis.

• D. Pulmonary toxicity:

• This is a rare complication.

• Children who are being maintained on MTX may

develop cough, dyspnea, fever, and cyanosis.


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• E. Neurologic toxicities:

• These are associated with intrathecal administration of MTX and include subacute meningeal irritation, stiff neck, headache, and fever.

• Rarely, seizures, encephalopathy, or paraplegia occur.

• Long-lasting effects, such as learning disabilities, have been seen in children who received the drug by this route.


Pharmacy 10-01-17 146

• Contraindications:

• Because MTX is teratogenic in experimental

animals and is an abortifacient, it should be

avoided in pregnancy.

• [Note: MTX is used with misoprostol to induce

abortion.]


Pharmacy 147

2. Purine antagonists Mercaptopurine (6-MP)

• The drug 6-mercaptopurine (6-MP) is the thiol

analog of hypoxanthine.

• 6-MP is used principally in the maintenance of

remission in acute lymphoblastic leukemia.

• 6-MP and its analog, azathioprine, are also

beneficial in the treatment of Crohn's disease.


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1. Nucleotide formation:

• To exert its antileukemic effect, 6-MP must penetrate target cells and be converted to the nucleotide analog, 6-MP-ribose phosphate.

• The addition of the ribose phosphate is catalyzed by the

salvage pathway enzyme, hypoxanthine-guanine

phosphoribosyl transferase (HGPRT).

HGPRT

• 6-MP 6-MP-ribose phosphate


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Ribose phosphate

2. Inhibition of purine synthesis:

• A number of metabolic processes involving- purine biosynthesis and interconversions, are affected by thioinosine monophosphate (TIMP) (a nucleotide analog).

• TIMP can inhibit the first step of de novo purine-ring biosynthesis (catalyzed by glutamine phosphoribosyl pyrophosphate amidotransferase).

• TIMP also blocks the formation of AMP and xanthinuric acid from inosinic acid.


Pharmacy 10-01-17 150

3. Incorporation into nucleic acids:

• TIMP is converted to thioguanine monophosphate (TGMP), which after phosphorylation to di- and triphosphates can be incorporated into RNA.

• The deoxyribonucleotide analog that are also formed are incorporated into DNA.

• This results in nonfunctional RNA and DNA.


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Resistance:

• Resistance is associated with

• 1) an inability to biotransform 6-MP to the corresponding nucleotide because of decreased levels of HGPRT (for example, in Lesch-Nyhan syndrome, in which patients lack this enzyme),

• 2) increased dephosphorylation, or

• 3) increased metabolism of the drug to thiouric acid or other metabolites.


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Adverse effects:

• Bone marrow depression is the principal toxicity.

• Side effects also include anorexia, nausea, vomiting, and diarrhea.

• Occurrance of hepatotoxicity in the form of jaundice has been reported in about one-third of adult patients.


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Pyrimidine antagonist

5-Fluorouracil (5-FU)

• Is converted in the body to the corresponding

nucleotide 5-fluoro-2-deoxy uridine monophosphate, which inhibits thymidylate synthase and blocks the conversion of deoxyuridilic acid to deoxythymidylic acid.

• Thus depriving the cell of thymidine, one of the essential precursors for DNA synthesis.

• Fluorouracil itself gets incorporated into nucleic acids and this may contribute to its toxicity.


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• Even resting cells are affected, though rapidly multiplying ones are more susceptible.

• Used in slowly growing solid tumors (for example, colorectal, breast, ovarian, pancreatic, and gastric carcinomas).

• When applied topically, 5-FU is also effective for the treatment of superficial basal cell carcinomas.


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Mechanism of the cytotoxic action of 5-FU.

5-FU is converted to 5-FdUMP, which competes with deoxyuridine monophosphate (dUMP) for the enzyme thymidylate synthetase. 5-FU = 5-fluorouracil; 5-FUR = 5-fluorouridine; 5-FUMP = 5-fluorouridine monophosphate; 5-FUDP = 5-fluorouridine diphosphate; 5-FUTP = 5-fluorouridine triphosphate; dUMP = deoxyuridine monophosphate; dTMP = deoxythymidine monophosphate.

5-FdUMP=5-fluorodeoxyuridine monophosphate.

•5-FU is converted to 5-fluorouridine-5′-triphosphate (FUTP), which is then incorporated into RNA, where it interferes with RNA processing and mRNA translation. •5-FU is also converted to 5-fluorodeoxyuridine-5′-triphosphate (FdUTP), which can be incorporated into cellular DNA, resulting in inhibition of DNA synthesis and function. •Thus, the cytotoxicity of 5-FU is thought to be the result of combined effects on both DNA- and RNA-mediated events. Dr. Bharat Mishra, Nirmala College of

Pharmacy 10-01-17 157

Resistance &Adverse effects:

• Resistance is encountered when the cells have lost their ability to convert 5-FU into its active form (5-FdUMP) or when they have altered or increased thymidylate synthase levels.

• In addition to nausea, vomiting, diarrhea, and alopecia, severe ulceration of the oral and GI mucosa, bone marrow depression (with bolus injection), and anorexia are frequently encountered.

• An allopurinol mouthwash has been shown to reduce oral toxicity.

• A dermopathy (erythematous desquamation of the palms and soles) called the hand-foot syndrome is seen after extended infusions.


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NATURAL PRODUCT CANCER CHEMOTHERAPY DRUGS : Mitotic Inhibitors

VINCA ALKALOIDS

• Vincristine (VX) and vinblastine (VBL) are structurally related compounds derived from the periwinkle plant, Vinca rosea.

• New (and less toxic) agent is vinorelbine (VRB).


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Mechanism of Action • They are cell cycle specific and act in the

mitotic phase. • These are mitotic inhibitors, bind to

microtubular protein-'tubulin', • prevent its polymerization and assembly of

microtubules, cause disruption of mitotic spindle and interfere with cytoskeletal function.

• The chromosomes fail to move apart during mitosis: metaphase arrest occurs.

• Although the vinca alkaloids are structurally very similar to each other, their therapeutic indications, anti tumour activity and toxicity are different.


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Uses

• VX is used in the treatment of acute lymphoblastic leukemia in children, Wilms‘ tumor, Ewing's soft-tissue sarcoma, Hodgkin's and non-Hodgkin's lymphomas, as well as some other rapidly proliferating neoplasms.

• VBL is administered with bleomycin and cisplatin for the treatment of metastatic testicular carcinoma.


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• It is also used in the treatment of systemic Hodgkin's and non-Hodgkin's lymphomas.

• VRB is beneficial in the treatment of advanced non small cell lung cancer, either as a single agent or with cisplatin.

• Adverse effects

• Both VX and VBL have certain toxicities in common.

• These include phlebitis or cellulitis during injection, as well as nausea, vomiting, diarrhea, and alopecia.

• Granulocytopenia is dose limiting for VRB.


Pharmacy 10-01-17 163

• VBL is a more potent myelosuppressant than VX, whereas peripheralneuropathy (paresthesias, loss of reflexes, foot drop, and ataxia) is associated with VX.

• The anticonvulsants phenytoin, phenobarbital, and carbamazepine can accelerate the metabolism of VX, whereas the azole antifungal drugs can slow its metabolism.


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EPIPODOPHYLLOTOXINS

Etoposide

• It is a semisynthetic derivative of podophyllotoxin, a plant glycoside.

• It is not a mitotic inhibitor, but arrests cells in the G2 phase and causes DNA breaks by affecting DNA topoisomerase II function.

• While the cleaving of double stranded DNA is not interfered, the subsequent resealing of the strand is prevented.

• It has been primarily used in testicular tumours, lung cancer, Hodgkin's and other lymphomas, carcinoma bladder.

• Alopecia, leucopenia and g.i.t. disturbances are the main toxicity.


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CAMPTOTHECIN ANALOGUES

• Topotecan and Irinotecan are two recently introduced semisynthetic analogues of camptothecin, an anti tumour principle obtained from a Chinese tree (Camptotheca acuminata).

• They act in a manner similar to etoposide, but interact with a different enzyme (DNA topoisomerase 1).

• Their binding to this nuclear enzyme allows single strand breaks in DNA, but not its resealing after the strand has untwisted.

• They damage DNA during replication; act in the S phase and arrest cell cycle at G2 phase.


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• Topotecan is used in metastatic carcinoma of ovary and small cell lung cancer after primary chemotherapy has failed.

• The major toxicity is bone marrow depression, especially neutropenia.

• Other adverse effects are pain abdomen, vomiting, anorexia and diarrhoea.


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• lrinotecan is a prodrug; is decarboxylated in liver to the active metabolite.

• Cholinergic effects are produced in some patients because it inhibits AChE.

• These effects can be suppressed by prior atropinization.

• Irinotecan is indicated in metastatic/ advanced colorectal carcinoma, cancer lung/cervix/ovary, etc.

• Dose limiting toxicity is diarrhoea; neutropenia, thrombocytopenia, haemorrhage, bodyache and weakness are the other adverse effects.


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Miscellaneous Drugs lmatinib

• It acts as a signal transduction inhibitor, inhibits the tyrosine protein kinases in chronic myeloid leukaemia (CML) cells and other tumers activated by platelet derived growth factor (PDGF) receptor, stem cell receptor and c-kit receptor found in gastrointestinal stromal tumour (GIST), a rare tumour.

• Stricking success has been obtained in chronic phase of CML as well as in accelerated phase, and in metastatic kit-positive GIST.

• Adverse effects are fluid retention, edema, vomiting, abdominal pain, myalgia and liver damage.


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References

• Robbins.; Basic Pathology. 7th edition, Elsevier, publication 2007; 641-655.

• Dipiro JT.; Pharmacotherapy, A Pathophysiologic Approach. 6th ed. Mcgraw hill medical publishing division 2005; 1333-1368 .

• Rang HP, Dale MM.;Pharmacology ;6th ed. Elsevier publication 2007:97-409

• Harvey A. Richard ;Pharmacology. 4th edition.Lippincotts illusrative review.

• Goodman & Gilman's the pharmacological basis of therapeutics - 11th ed. (2006).

• Kd tripathi ;essentials of medical pharmacology ,sixth edition. jaypee brothers medical publishers (p) ltd.2008.

• Bertram Katzung, Susan Masters, Anthony Trevor Basic and Clinical Pharmacology, 12E. 2011.


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