cancer general and therapy

7/30/2019 Cancer general and therapy

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CANCER GENOMICS


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A scale of the cancer problem

Cancer type Birth-39 40-59 Birthdeath

All cancers, 1/69 1/52

Male/Female

1/12 1/11

Male/Female

1/2 1/3

Male/Female

Breast 1/229 1/24 1/8Uterine corpus 1/567 1/288 1/117

Uterine cervix 1/2097 1/138 1/37

Prostate


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AGE-ADJUSTED CANCER DEATH RATES

(Males)

Last 70 years statistics

LUNG CANCERUP!!!

10 times (due to smoking

and air pollution)

GASTRIC CANCER -

down 4 times

REASON?better nutrition?

Probably


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AGE-ADJUSTED CANCER DEATH RATES

(Females)

Last 70 years statistics

LUNG CANCERUP!!!

10 times (due to smoking

and air pollution)

GASTRIC CANCER -

down 4 times

Same as in males.

UTERINE CANCER

(including cervix)

down 5 times due to

early diagnostics


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Does science help patients?

5-year survival rates

Year 92-97Years 83-85Years 74-76Cancer type

86%85%89%Uterine corpus

6%6%4%Liver

4%3%3%Pancreas

NO!

97%76%68%Prostate46%42%35%Leukemia

87%79%75%Breast

Year 92-97Years 83-85Years 74-76Cancer type

YES!


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HOW SCIENCE CAN HELP

CANCER PATIENTS?

Early diagnosis Specific treatment

Early check for relapse

NOT possible without understanding

of the state of genes in every given tumor

Few things contribute


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Tumors are very polymorphic entities

Multiple systems of tumor classification exist

Breast cancer

Brain cancer

Liver cancer

Colon cancer

Carcinoma

Sarcoma

Lymphoma

Mucinous cystadenocarcinoma

Carcinomas with spindle

and/or giant cells

ORGANbased

(trivial)WISDOMbased

(cliniciansexperience)

TISSUE - based

(histological)

Grading/staging

(metastase/invasion)1

There is no such a thing like tumor in general;

they all differ in their way to survive and kill

Pace of progression

(slow of fast)2

(best working)


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ORGANbased classification

Breast cancer as an example

Tumors can be derived

from ductal cells or lobular cells

Invasive carcinomas (ductal or lobular or even mixed)

Ductal carcinoma

in situ (DCIS)

Lobular carcinoma

in situ (LCIS)

?

inflammatory breast cancer, medullary carcinoma, mucinous carcinoma,Paget's disease of the nipple, Phyllodes tumor, and tubular carcinoma.

malignant benign

Very malignant

High chances to become Low chances to become


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TISSUE-based classification

Carcinomamalignant neoplasm of epithelial origin,including internal epithelium(bladder lining, pancreatic duct lining etc. )

Adenocarcinoma

From tissue/cellsproducing secret

milk or mucous or enzymes

Other small variants, like basal cell carcinoma etc.

Squamous cell carcinoma (SCC)

From pure lining cellsor from skin epithelium


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Sarcoma

Sarcoma refers to cancer that originates

in supportive and connective tissuessuch as bones, tendons, cartilage, muscle, and fat.

Osteosarcoma or osteogenic sarcoma (bone)Chondrosarcoma (cartilage)Leiomyosarcoma (smooth muscle)Rhabdomyosarcoma (skeletal muscle)Mesothelial sarcoma or mesothelioma

(membranous lining of body cavities)

Fibrosarcoma (fibrous tissue)Angiosarcoma or hemangioendothelioma (blood vessels)Liposarcoma (adipose tissue)Glioma or astrocytoma (neurogenic connective tissue

found in the brain)Myxosarcoma (primitive embryonic connective tissue)


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Leukemia

cancers of the bone marrow (liquid phase)

overproduction of immature lymphocytes, whichdo not perform as well as they should, therefore

the patient is often prone to infection

lymphocytic

Myelocytic/myelogenouserythroblastic

Mixed (polycytemia vera)


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Lymphoma

tumors from the lymphocytes from lymph nodes(solid tumors)

Can be present in extranodal (non-lymph nodes) sites

stomach lymphoma, skin lymphoma.

Lymphoma goes through the same stages of generalization

(metastase) as any solid tumor

Hodgkin disease Non-Hodgkin lymphoma


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Teratoma

Mixed type of tumor,

often it is derived from embryonic or stem cells

The most common elements

are components of

stratified squamous epithelium

medstat.med.utah.edu/


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Common types of cancer progression

Adenocarcinoma

Squamous cell carcimoma

Liposarcoma

Fibrosarcoma

Glioblastoma multiforme

Acute leukemic crisis (blast crisis)

Adenoma

Papilloma

Glioma

Lipoma

Fibroma

Anaplastic glioma

Remission with latent residual diseaseChronic leukemia


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WISDOMbased classification of

tumors

BENIGN MALIGNANT

No invasion Invasion

Borders No clear borders

Normal blood vessels

many leaky blood vessels

newscenter.cancer.gov/sciencebehind/ cancer/cancer34.htm
http://newscenter.cancer.gov/sciencebehind/cancer/cancer34.htmhttp://newscenter.cancer.gov/sciencebehind/cancer/cancer34.htm


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Histological picture of

tumor malignisation



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TUMOR GRADES are based on

degree of cell differentiation

Grade I

(Cells are slightly abnormal and well differentiated)

Grade II

(Cells are more abnormal and moderately differentiated)

Grade III(Cells are very abnormal and poorly differentiated)

Grade IV

(Cells are immature and undifferentiated)

tumor cells obtained from biopsy are

evaluated by histopathologist


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Tumor histology

Metaplasia

Replacement of normal differentiated tissue by another

(differentiated) type like epithelial to mesenchime

transition in breast carcinoma progression

Anaplasia

Loss of differentiated phenotype

DysplasiaLoss of tissue organisation

Hyperplasia

Increase in cell division


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The tumor, nodes, metastases (TNM) system

classifies cancer :

-- by Tumor size,-- the degree of regional spread or Node

involvement

-- and presence/absence of distant Metastasis.

TUMOR STAGING

Staging is the classification of the extent of

the disease in the body.

Most common systems are TNM system and Numerical system

T

MN


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Tumor (T)

T0 (No evidence of tumor)

T14(Increasing tumor size and involvement)

Tis(Carcinoma in situlimited to surface cells)


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Node (N)

N0 No lymph node involvement

NxLymph node involvement cannot be assessed

N14Increasing degrees

of lymph node involvement


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Metastases (M)

M0 No evidence of distant metastasesM1 Evidence of distant metastases

www.ikp.unibe.ch/lab2/cytostatics/ sld014.htm

Pancreatic carc. met. in liver
http://www.ikp.unibe.ch/lab2/cytostatics/sld014.htmhttp://www.ikp.unibe.ch/lab2/cytostatics/sld014.htm


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Numerical system

Stage 0 Cancer in situ (limited to surface cells)

Stage 1 Cancer limited to the tissue oforigin with evidence of tumor growth

Stage 2 Limited local spread of cancerous cells

Stage 3 Extensive local and regional spread

Stage 4 Distant metastasis


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Grading / Staging and prognosis


High-grade tumors progress faster Late-stage tumors prognosis is worse


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CANCER TREATMENT

IDEAL GOAL:

Completely eradicate tumor

ATTAINABLE GOAL:

Remove primary tumor

(surgically)

or achieve tumor shrinkage

(chemotherapy)

Radical Palliative

GOALS:

Pain relief

Infection combat(especially important

for leukemias and lymphomas)

Chemo-related

problems combat


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RADICAL STRATEGIES of the

TUMOR TREATMENT

Surgery Chemotherapy

IMMUNOTHERAPY

Radiotherapy

Hormonal therapy


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SURGICAL REMOVAL

MINUSES:

-Not able to catch and remove micrometastases;

-Not able to deal with ascytic (liquid) tumors

Primary care for most of the tumors

On the advanced stages surgery

always used in combination with

chemotherapy

Ablastic principle (all cuts are done within normal

tissue; can be PCR controlled)


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CHEMOTHERAPY

CHEMOTHERAPY is the treatment of

cancer with drugs that can destroy cancer

cells.

Ideal anticancer drug should be able to

kill tumor cell and be harmless for any

normal cell

Problem:

No clear differences between normal and tumor cells


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FIRST PROBLEM WITH CHEMO =

side effects

Only the rate of cell division makes tumor cell

more prone to poisonous effect of

chemotherapy

Normal cells with fast pace of divisions

are also very susceptible to chemo

Side effects for BONE MARROW, COLON,

HAIR FOLLICLES etc.

(Cytoreduction)


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SIDE EFFECTS of Chemotherapy

Oral mucosa toxicity

mucositis (oral dryness)

Hair follicle toxicity

hair loss

Bone marrow toxicity

infection and hemorrhage (bleeding)

Gut mucosa toxicity

diarrhea


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Genomics can help!

Better understanding of differences

between normal and tumor cells

can help to invent new drugs

with increased tumor-specific action


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SECOND PROBLEM WITH CHEMO

= tumor resistance

After rounds of chemotherapy and successful

shrinkage of tumor and/or remission tumor

cells become resistant to treatment

Side effects prevail over benefits

Clinician has to stop treatment

and tumor start to grow again


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Genomics can help again!

Understanding of genomic changes during

development of resistance

can help prevent such changes

or help invent new drugs

not producing common types of resistance


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Traditional chemotherapeutic drugs

I. Alkylating agents (e.g. cisplatin)

II. Antimetabolites (e.g. Folate, purine or

pyrimidine analogs) III. Plant derivates (vinca alcaloids,

taxanes, etoposide)

IV. Anti-tumoral Antibiotics

Tumor could become resistant

to any of this compounds or their combinations


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I. Alkylating agents:

Nitrogen mustards, Nitrosoureas,Platinum agents (Cisplatin), Cyclophosphamides

The alkylating agents react with everything;

impair cell function by formingcovalent bonds with the amino, carboxyl, sulfhydryl,

and phosphate groups in biologically important molecules

Alkylating agents generally interact with DNA non-specifically:the more effective ones tend to crosslink DNA.

The electron-rich nitrogen at the N7 position of guanine

in DNA

is particularly susceptible to alkylation.


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Monoalkylation

Crosslinking

(Between strands)

Crosslinking

(Same strand)

chlorambucil and melphalan

Cis-platinum

Therefore Alkylating Agents can be used

for the treatment of slow-growing tumors;

extensive damage of DNA will lead to cell death

Alkylating agents

interact with DNA

non-specifically

Active even

for the resting cells

(not cell cycle/phase-specific)

(damage cell now,

kill it during next cell

division)

Nitrogen mustard first chemotherape tic


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Nitrogen mustardfirst chemotherapeutic

substance (interstrand-linking agent)

Nitrogen mustard drugs were developed from mustard gas,a war agent first used during the First World War at Ypres.

One of the toxic-effects of exposureis the destruction of the bone marrow and white blood cells.

Could penetrate all protective materials except urethan

Cure for cancer of the lymph glands

Hodgkin's Disease.

Mustard gas

Nitrogen mustard

Cisplatin


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BETTERthan INTERstrand-linking agent!!

because of two reasons

Cisplatin(Same strand-linking agent)

Cisplatin


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Cisplatin(Same strand-linking agent)

Cisplatin Therapy Type of CancerComplete cure Testicular cancer

Sensitive Ovarian

Responsive Bladder, Head & neck

Resistant Cervix, Prostate, Esophegeal

Activity shown Various, eg.: Non-small cell lung,

Ostegenic sarcoma, Hodgkins lymphoma

1. Same strand cross-links formed are harder" to repairthan cross-links between strands.

2. Cisplatin is able to replace zinc(II) ion in zinc-finger containing

transcription factors, directly destroying transcription regulation

Synergy shown in combination with 5-fluorouracil, cytarabine and bleomycin,That allows for greater flexibility in the design of drug regimens.

T ld d l i t t


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Tumor could develop resistance to

alkylating agents

-- Increase in glutathione synthesisconjugation with glutathione leads to chemical

inactivation of alkylating agents

(catalyzed by glutathione S-transferase)

Genomic changes in AA treated tumor cells may lead to:

-- Increase in ability of treated cells to repair DNA defects;

-- Decrease in cellular permeability

to the Alkylating drugs;


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1. Antimetabolites are structural analogs of the naturallyoccurring metabolites involved in DNA and RNA synthesis.

2. Antimetabolites exert their cytotoxic activityeither by competing with normal metabolites for the

catalytic or regulatory site of a key enzymeor by direct substituting for a nucleotide

that is normally incorporated into DNA and RNA.

3. Antimetabolites are most active in S phasecellsand have little effect on cells in G0.

Consequently, these drugs are

most effective in rapidly dividing tumors

II. Antimetabolite agents:


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Pyrimidine analogs -- Flurouracil (5-FU), Ara-C(inhibits enzymes involved in pyrimidine metabolism)

Types of Antimetabolites:

Folate analogs -- Methotrexate (MTX)(bind to catalytic site of dihydrofolate reductase DHFR)

Purine analogs -- Mercaptopurine,Fludarabine

(inhibits enzymes involved in purine metabolism)


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Methotrexate (MTX)

www.vet.purdue.edu/

Looks very same

to folic acid

necessary nutrient.

No THF-co-enzymes

for one-carbon transfer

No production of

tetrahydrofolic acid

No de novo purines and pyrimidines

Broad rangeTreat leukemia, lymphomas, and osteosarcoma.

It is also used in the treatment of AIDS and rheumatoid arthritis

No DNA synthesis

DHFR like MTX

more than folic acid

Methotrexate

Methotrexate (MTX) resistance as an


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Methotrexate (MTX) resistance as an

example of antimetabolite resistance

Genomic changes in MTX-treated tumor cells may lead to:

-- decrease in drug transport into the cell (less MTX)

-- alteration in gene DHFR encodingdihydrofolate reductase enzyme with lower affinity for

methotrexate(MTX-durable DHFR)

-- quantitative increase in DHFR concentration

by DHFR gene amplification,

or by increased DHFR mRNA production

(more DHFR)


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III. Plant derivates (heterogenous group)

Vinca alcaloids (Vinblastine, Vincristine)

from periwinkle plant Vinca rosea(native to Madagaskar);

Taxanes (Paclitaxel = Taxol and docetaxel = Taxotere) from

needles of Pacific Yew plant Taxus brevifolia;

Podophyllotoxin (etoposide) from

Podophyllum peltatum (India)

Camptothecins (topotecan, irinotecan)

from Cam totheca acuminata (China)

Vinblastine
http://www.plantbio.uga.edu/herbarium/herbarium/gaflowers/Podophyllum%20peltatum%20flr.jpghttp://www.botanik.uni-bonn.de/conifers/ta/ta/brevifolia3.jpg


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Vinblastine,

Vincristine

Cells are arrested at metaphaseas no chromosome segregation possible

-- Mechanism of action = mitosis block:bind to tubulin and induce microtubule depolymerization (Disassembly)

http://www.img.cas.cz/dbc/gallery.htm

ouse 3T3 fibroblast (normal) 3T3 after vincristine

Redanti-tubulin;

Greenanti-vimentin;

Blue -- DNA

Vinca alcaloids bind to tubulin dimers


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www.staff.ncl.ac.uk/i.r.hardcastle/ antibiotics.html

at a specific recognition site on the protein.

Tubulin form paracrystaline aggregates

Concentration of the free dimers is reduced

Equilibrium of growth/shrinkage of tubules shifted to the shrinkage

Mitotic spindlescan not be formed

P li l (T l)

www.chem.wisc.edu/~bestchem/ taxol.gif
http://www.staff.ncl.ac.uk/i.r.hardcastle/antibiotics.htmlhttp://www.staff.ncl.ac.uk/i.r.hardcastle/antibiotics.html


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Paclitaxel (Taxol)

and docetaxel (Taxotere)

-- Mechanism of action = mitosis block:

promote microtubule assembly and super stability,

action is opposite to vinca alcaloids, but effect is the same

Used for treatment of otherwise resistant ovarian cancers

and recurrent breast tumors

+ Taxol

Bundling of accumulated, disorganised microtubule filaments.

Podophyllotoxin (etoposide) =


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Etoposide inhibit

topoisomerase IIthat catalyses

transient breaking

and re-joining

of ds DNA strands

(DNA becomes damage

Both ends of DNA can freely rotate

within the enzyme

Reconnection

of DNA

Etoposide stabilizes

TOPO II DNA complex

in non-sealable form

odop y oto (etopos de)

Topo II inhibitor

Camptothecins


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Camptothecins

(topotecan, irinotecan) =

Topo I inhibitor

Topotecan binds to the topoisomerase I-DNA complex

and prevents ligation of the DNA strand,

resulting in DNA breakage during the elongation and cell death

topoisomerase I produces

reversible single-strand breaks in DNA

These single-strand breaks relieve torsional strains,and allow DNA replication to proceed.

TOPO I is not required for the viability of cells (TOPO II can substitute).

Therefore, TOPO Inegative cancer cells are viable

and resistant to topotecan

IV. Antitumoral antibiotics


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IV. Antitumoral antibiotics

(produced by fungi)Anthracyclines:

Doxorubicin (Adriamycin) and Daunorubicin

Bleomycin

Produced byStreptomyces verticillusas a mixture of small-molecular-weight

copper-chelating glycopeptides

Produced by fungus

Streptomyces percetusvar caesius.

Doxorubicin Bleomycin


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Anthracyclines:Doxorubicin (Adriamycin) and Daunorubicin

Active in Hodgkin's disease, non-Hodgkin's lymphomas, sarcomas,

acute leukemia, and breast, lung, and ovarian carcinomas

Mechanisms of action:

1) intercalation between DNA base pairs

and inhibition of DNA topoisomerases I and II.

2) Altering membrane fluidity and ion transport


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Mechanisms of action - multiple:

1) binds to double- and single-stranded DNA

produces site-specific and non-specific SS and DS breaks

ratio single:double = 10:1; Cleave DNA at G-C and G-T sequences;

DNA in open chromatin esp. sensitive (where genes are expressed)

Bleomycin

Rapidly degraded by bleomycin

hydrolase

present in most tissues

except skin and lung

3) Inhibits DNA reparation by suppression of DNA ligase

2) Makes non-covalent interstrand links

No bone marrow

and intestinal toxicity!!

(Pulmonary fibrosis

and skin effects are strong...)

M l id i h


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Multidrug resistance phenomenon

Is a membrane associated phenomenon

that represents a serious obstacle to chemotherapy of cancer

Cell that are treated with (lets say) etoposide

and develop resistance to etoposide,

simultaneously become resistant to Methotrexate

MDR caused by induction of membrane proteins that

effectively and (almost) non-specifically expel

small molecules from the cell!

P-glycoprotein (170 kDa)

Belongs to traffic-ATPase superfamily

of transport proteins

Other transporters

BCRP, ABC 1,2,3 etc.

P-glycoprotein


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This is an ATP-dependentexport pump (= efflux pump)

of broad specificity

This efflux pump expelhydrophobic drugs,

natural products and peptides.

The transport function of P-glycoprotein can be blocked

by the action of another group of compounds

known as MDR modulators, or chemosensitizers

cyclosporin A, verapamil, tamoxifen

P glycoprotein



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TUMOR TREATMENT


IMMUNOTHERAPY

Radiotherapy

Hormonal

therapy


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RADIOTHERAPY

General principle is the samereduce a massof rapidly dividing cells (cytoreduction

principle, the same as for chemo)

Differenceradiotherapy is regional.

IR could be focused like a beam of light

to a treated area (internal or external)

Side effects are the same as for chemo

HORMONAL THERAPY


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HORMONAL THERAPY

Good for hormone-dependent tumors

Estrogens are trophic factors for breastepithelium and uterine epithelium

Speaking generally, hormonal therapy can be discussed

as trophic factor removal therapy

Removal of estrogen

from ER-positive tumors

leads to stop of their growth

Tamoxifen Tamoxifen mimics


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(Nolvadex)the action of estrogene

and binds to estrogen receptor (ER).

DNA-tamox-ER complex is unable to functionin the same way as the DNA-estrogene-ER complex

The tamoxifen-ER complex dimerises

Than transported from the cytosol

into the cell's nucleus

The dimeric tamoxifen-ER complex

binds to DNA

!!!! In other tissues of the body Tamoxifen

plays exactly like estrogene itself !!!

In reality mechanism is not known completely


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IMMUNOTHERAPY

Cytokines: IFN-alpha, IL-2, Tumor necrosis factors (TNFs)

Any intervention to enhancethe body's natural ability

to defend itselfagainst malignant tumors.

Monoclonal antibodies: anti-CD20 Rituximab for lymphomas,anti-HER2 trastuzumab (herceptin) for breast cancer

Cancer Vaccines: cancer-specific antigens +other components boosting immunity (e.g. dendritic cell vaccines)


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RADICAL TUMOR

TREATMENT STRATEGIES

IMMUNOTHERAPY


Radiotherapy

Hormonal therapy

MODERN science-oriented

therapies

Modern science for cancer treatment


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Modern science for cancer treatment

improvement

SURGERYPCR assisted surgery

IMMUNOTHERAPYentirely modern area

HORMONAL THERAPYdesignedchemical inhibitors of hormone receptors

RADIOTHERAPYnormal (p53 positive) cell

can be protected by p53 inhibitor pifithrin

CHEMOTHERAPYnew target-specific drugs,

tumor-specific delivery

cancer general and therapy

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