Anticancer and Chemotherapy

By:Mohamed Fahad Al-Ajmi

INTRODUCTION

Definition:

Under the influence of chemicals in the environment, radiation or viruses, the DNA in normal cells may be transformed, possibly by a single alteration or substitution of one of the constituent purine bases, in such a way that the normal control mechanisms, which restrict cell proliferation are removed.

INTRODUCTION Cancer incidence and death by organ sites

Most common new cancer cases:Male: Female:

Prostate (29%) Breast (30%)Lung (15%) Lung (13%)Colon/rectum (10%) Colon/rectum (11%)

Leading cancer deaths:Male: Female:Lung (32%) Lung (25%)Prostate (13%) Breast (16%)Colon/rectum (9%) Colon/rectum

(11%)

INTRODUCTION

Terminology Hypertrophy:is the increase in size of a

tissue or organ through increase in the size of the consistuent cells.Hyperplasia:is the increase in organ or

tissue size through increase in cell number. Both hypertrophy and

hyperplasia are reversible on removal of the growth stimuli

INTRODUCTION

Nomenclature

CARCINOGENESIS

The process by which a normal cell is converted to a cancer or malignant cell.

CARCINOGENESIS

Before discussing the details of molecular basis of CARCINOGENESIS we need to now how a normal cell divide (cell cycle).

The eukaryotic cell cycle

M

G0

G1

S

G2

M: Mitosis

S: Synthesis

G1, G2: Gaps between M and S

G0: Quiescent phase

DNA content change in cell cycle

Checkpoints: Point in the eukaryotic cell cycle where progress through the cycle can be halted until conditions are suitable for the cell to proceed to the next stage.

M

G0

G1

S

G2

DNA damageIncomplete

DNA replication

Chromosomes Unattached to the spindle

DNA damageUnfavorable

growth conditions

G1 checkpoint

G2 checkpoint

Mitotic checkpoint

Relationship of antitumor drug action to the cell cycle

CARCINOGENESIS

Causes of cancer

CARCINOGENESIS

Causes of cancer: Radiation

Ionizing radiationUV light.

VirusesPapelloma virus AIDS virusHepatitis virus

Major classes of anti-cancer drugs

Alkylating agents

Antimetabolites

Antibiotics

Antimitotics

Hormones and antagonists

Molecularly-targeted therapy

Alkylating agents

Damage DNA in resting and cycling cells Most toxic to rapidly proliferating cells

Cell-cycle nonspecific. Toxicities include bone marrow

suppression, acute and delayed GI effects Example: cyclophosphamide (Cytoxan)

May cause hemorrhagic cystitis, particularly in dogs

Keep well hydrated, encourage drinking

Alkylating agents

Mechanism of action: cross-link 2 strands of DNA leading to impairment of DNA replication and RNA transcription.

Alkylating agents: examples

cyclophosphamide: creates guanine adducts that block cell proliferation.

cisplatin and its analogues, such as oxaliplatin: form DNA adducts and create inter or intrastrand crosslinks that disrupt DNA synthesis.

Antimetabolites

Analogues of normal metabolites, incorporated into DNA or RNA, resulting in abnormal nucleic acids and inhibition of enzymes involved in nucleotide biosynthesis

Purine Synthesis

Pyrimidine Synthesis

Ribonucleotides Deoxyribonucleotides DNA

RNA

Antimetabolites

Act in G1, S, G2 or M phases Effective for high growth fraction

cancers

Antimetabolites

Act the S phase: inhibit DNA synthesis Example: methotrexate

Mimics folic acid, which is needed for synthesis of DNA, RNA and some amino acids

Toxicities include delayed GI effects and bone marrow suppression

Antimetabolites: examples

Methotrexate: a folate analog inhibits dihydrofolate reductase (DHFR), the enzyme essential for nucleic acid synthesis.

5-fluorouracil (5-FU): a pyrimidine analog that inhibits thymidylate synthase and also interferes with RNA synthesis and function.

Gemcitabine: a pyrimidine analog that inhibits DNA polymerase.

FH2: dihydrofolateFH4: tetrahydrofolate TMP: thymidine monophosphatedUMP: deoxyuridine monophosphate

5-FU

Methotrexate

DNA

Antibiotics Bacterial or fungal derivatives, Mechanism of action:

intercalates within the DNA, causes single and double strand breaks, and inhibits topoisomerase II.

Damage DNA in cycling and noncycling cells.

Examples:1- Bleomycin:

Antibiotics

2- doxorubicin (Adriamycin) Rapid IV administration causes histamine release, severe pruritis and swelling (facial). Pretreat with H1 and H2

receptor antagonistsProduces free radicals that damage heart muscle, particularly in dogsVesicant

Inhibitors of topoisomerases

Topoisomerases: Cleavage, unwinding and re-annealing of DNA, necessary for DNA replication and RNA transcription

Etoposide (VP-16): Inhibits topoisomerase II, leading to double-strand DNA breaks

Etoposide

Antimitotics

Mechanism of action: natural products that interfere with

microtubule synthesis and degradation, leading to inhibition of cell division.

Cell-cycle specific.

Examples: 1- Paclitaxel (Taxol): stabilizes

microtubules, inhibit the cell cycle during mitosis.

Antimitotics

2- Vinca (plant) alkaloids Act in M phase to inhibit mitosis Vincristine and vinblastine Both can cause bone marrow

suppression and neurotoxicity Vesicants: cause blisters on contact

with skin, extravasation causes tissue necrosis

Protective gear absolutely essential

Mechanism of antimitotics

Paclitaxel

Vinblastine

Hormones and antagonists

Mechanism of action: inhibits synthesis or effects of the steroid

hormones that are necessary for growth of certain tumors, such as breast and prostate tumors.

Examples: Tamoxifen: binds to estrogen receptors (ER) as an

antagonist inhibitor of estrogen. Anastrozole: inhibits aromatase, the enzyme that

catalyzes the final step in estrogen production.

Mechanisms of Tamoxifen

STI-571 (Gleevec, Imatinib)

A small molecule that inhibits Bcr-Abl tyrosine kinase

Targets this enzyme which is over-expressed in CML (chronic myeloid leukemia)

Taken by mouth daily for treatment of refractory CML

Gefitinib (Iressa)

It inhibits the intracellular tyrosine kinase (TK) domain of epidermal growth factor receptor (EGFR).

Recent research indicates that it inhibits growth of cancer cells with mutations of the TK domain of EGFR.

It is approved for treatment of non-small cell lung cancer refractory to standard chemotherapy. (~10% patients have EGFR mutations)

Antibodies

Herceptin (Trastuzumab)

A recombinant monoclonal antibody against epidermal growth factor receptor 2 (Her2); used for treating refractory breast cancer over-expressing HER2 protein

Avastin (Bevacizumab)

A recombinant monoclonal antibody against VEGF, which plays an important role in blood vessel formation (angiogenesis); used for treatment of colon cancer

Enzymes

L-asparaginase Breaks down blood asparagine – needed

by some cancer cells for protein synthesis Used against lymphomas and some

leukemias Antigenic (large protein): hypersensitivity

reactions common

Side effects of chemotherapy

Common toxicities of chemotherapy

Organs with active cell division are affected: Bone marrow GI tract mucosa Hair follicles

These side-effects are often reversible.

Common toxicities

Bone marrow suppression:

Leukopenia, thrombocytopenia and anemia

Caused by most anti-cancer drugs except: Bleomycin, vincristine, hormones, and most of the molecularly-targeted agents.

Common toxicities Gastrointestinal toxicity:

Nausea and vomiting: cisplatin and anthracyclines Diarrhea: 5-FU, topotecan Mucositis: 5-FU

Alopecia (Hair loss): Paclitaxel, carboplatin, anthracyclines.

Renal toxicity: Cisplatin

Pulmonary toxicity: Bleomycin (pulmonary fibrosis)

Peripheral neuropathy: Cisplatin, oxaliplatin and paclitaxel

Long-term complications

Cardiomyopathy: Anthracyclines (Incidence exceeds

5% for high-dose of doxorubicin)

Leukemia: high-dose etoposide

Infertility: Alkylating agents

Management of side-effects

Use antiemetics to prevent nausea/emesis e.g. Zofran; a serotonin antagonist

Anemia Blood transfusion and/or erythropoietin (Epogen)

Neutropenia: Granulocyte-colony-stimulating factor (G-CSF,

Neuprogen) To shorten duration of neutropenia

Thrombocytopenia: Platelet transfusion and/or thrombopoietin

Guidelines for handling/administering chemotherapeutic agents

Wear latex gloves, surgical mask, goggles, protective clothing (eg, lab coat) when handling

Dilute or mix drugs under laminar flow hood (if available) or in low-traffic area without air currents. This helps prevent aerosolization of particles

Try to use drugs available as preservative-free solutions to avoid having to dilute them

Guidelines for handling/administering chemotherapeutic agents

If drug must be diluted, use needle guard (available from manufacturers)

Never “prime” needle by squirting drug into air

Never use mouth to remove needle cap Administer drugs through IV catheter to

avoid extravasation Place carefully and check throughout infusion

Guidelines for handling/administering chemotherapeutic agents

Guidelines for handling/administering chemotherapeutic agents

Pregnant women should not handle/administer antineoplastic agents

Thoroughly wash hands before and after handling/administering antineoplastic agents

Prevent contact of agent with skin or mucous membranes. If this occurs, wash area immediately with large volumes of water, document the contact and seek medical assistance

Guidelines for handling/administering antineoplastic agents

Place absorbent pad under patient’s leg If drug spills, allows disposal of pad

without contaminating table Wear latex gloves when disposing of

vomit, urine or feces from animals receiving antineoplastic agents

Maintain record of all exposure during preparation, administration, clean-up and spills