Pharmacology - Cancer Therapy (B63-64)

Front 1

7 groups of drugs for cancer therapy

Back 1

1. Alkylating agents

2. Antimetabolites

3.Plant alkaloids

4. Antibiotics

5. Hormones

6. Platinum compounds

7. Misc. agents

also interferons

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What are the alkylating agent drugs?

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Cyclophosphamide and Ifosamide

Mechlorethamine

Chlorambucil

Nitrosureases

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Mechanism of alkylating agents?

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Binds covalently to nucleophilic groups

(the alkyl groups; ethyleneimine ions & +ve charge carbonium ions) are highly reactive so bind.

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Cyclophosphamide and Ifosamide

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can be taken orally,

broad clinical spectrum,

drugs are biotransformed to hydroxylated intermediates by CYP450,

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adverse effect of cyclophosphamide and ifosamide,

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bone marrow depression and hemorrhagic cystitis

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Use of chlorambucil

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for chronic lymphocytic leukemia

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Nitrosoureas

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addition to alkylating they also inhibit some enzymes,

have limited use in treatment of other cancers,

drugs penetrate CNS so can treat brain tu,

kidney is major excretory route,

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Adverse effects of Nitrosoureas?

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Aplastic marrow, renal toxicity, pulmonary fibrosis,

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Mechlorthamine

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develop, as nitrogen mustard in WW1,

covalently attaches to two separate nucleotides and cross links the strands of DNA,

treatment of Hodgkins disease,

drug is only administered IV,

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What are the Antimetabolites (groups)?

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a) Folic acid antagonists

b) Pyrimidine antagonists

c) Purine antagonists

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Antimetabolites how

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Str. analogues of cellular metabolites,
selective for partial malignant cells,
usually phase specific,

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Methotrexate (MTX)

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competes with Folic Acid for active site, is a step-block preventing nucleic acid synth,

requires close monitoring for toxicity,

drug is administered orally, iv, im and it,

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What is MTX used against?

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Acute lymphocytic leukemia,

choriocarcinoma,

Burkitt lymphoma in children,

breast ca,

head and neck carcinomas,

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Adverse effects of MTX

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Nausea, vomitting, diarrhea, stomatits, myelosuppresion,

renal damage,

liver cirrhosis,

Pulmonary toxicity,

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What are the pyrimidine antagonists?

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5-fluoroucil (5-FU)

Cytosine arabinoside,

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5-fluoroucil (5-FU)

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pyrimidine analog,

has a fluorine atom instead of H-atom in uracil ring,

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Mechanism of 5-fluoroucil,

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fluorine interferes with the conversion of feoxyuridylic acid to thyidylic acid -> deprives cell of thymidine -> DNA synth. decr.

treats slow growing tu.
metabolized in liver, lung and kidney

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What is the purine antagonist for antimetabolites?

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6-mercaptopurine (6-MP)

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How does 6-mercaptopurine work?

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Penetrates target cells and are converted to nucleotide analogue and once converted to TIMP it has antileukemic effect.

TIMP inhibits first step in de novo purine-ring biosynth.

its taken orally

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6-thioguanine (6TG)

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another antimetabolite that treats nonlymphocytic leukemia. The products inhibit biosynth. of purines and phosphorylation of GMP to GDP.
(genotyping is req.before therapy because cytotoxic metabolites accumulate)

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Fludarabine

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Antimetabolite that is a purine nucleotide used in chronic lymphocytic leukemia, HCL, and non Hodgkins,

incorporates into DNA and RNA,

urinary excretion.

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Plant alkaloids

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interfere with mechanism of cell division and are:

Etopside and Vinca alkaloids

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How does etopside work?

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Blocks cells in late S to G2 phase and major target is topoisomerase ii.

used to treat cell carcinoma of lung and testicular cancer,

(affected by drugs that induce CYP450)

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Vinca alkaloids

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binds to tubulin that forms microtubules in separation of chromosome.

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How does antibiotics work in cytostatics generally?

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Through their interaction with DNA function and their ability to inhibit topoisomerase i and ii.

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What are the antibiotics used in cytostatics?

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Dactinomycin,

daxorubicin and daunorubicin,

bleomycin

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How do the anthracyclines; daxorubicin and daunorubicin work?

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they generate free radicals that destroy the DNA, the drugs are admin via IV.

they undergo extensive hepatic metabolism,

doxorubicin, used in treatment of sarcomas, carcinomas, acute lymphocytic leukemia, lymphomas

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How does bleomycin work?

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causes scission of DNA by an oxidative process, it is primarily used to treat testicular cancer (with combo of vinblastine and etoposide)

bleomycin Fe3+ undergo oxidation to Fe2+ and the free electron reacts with o2 to form the radical or h2o2.

main adverse effect is pulmonary toxicity.

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How do steroid hormones work in cytostatics?

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The tu. might be hormone responsinve and regresses and/or are hormone dependant.

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How does prednisone work?

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Use to treat lymphomas it binds to plasma proteins.

it is converted to prednisolone in the liver and is glucuronidated and excreted in the urine.

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How does tamoxifen work?

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Its an estrogen antagonist, in treatment to estrogen-receptor of breast cancer. binds to the receptors and fails to induce the estrogen responsive genes and RNA not produced and then natural estrogen is suppressed.

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What are the steroid hormones used for cancer therapy?

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Prednisone,

tamoxifen,

estrogens,

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Estrogens are used how in cancer therapy?

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are used to treat prostatic cancer, they inhibit the growth by blocking production of LH.

causes decr. synth of androgens in testis, so tu dependant on androgens are affected.

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How do monoclonal antibodies work in cancer therapy?

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They are directed at specific targets, and have fewer AE, created from b-lymphocytes and then fused with the tu b-cells.

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What are the microtubule inhibitors?

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Vincristine and vinblastine

Paclitaxel and docetaxel

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How does vincristine and vinblastine work?

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Known as vinca alkaloids and fn as such

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How does docetaxel work?

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By binding reversibly to beta-tubulin subunit and promotes polymerisation and stabilisation.

used to treat ovarian cancer, metastatic breast cancer.

hepatic metabolism by CYP450 system.

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Platinum compounds

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cisplatin; in DNA synth by formation of intra &interstrand cross links with DNA mol.

has wide application in treatment of solid tu, as metastatic testicular carcinoma, ovarian ca or for bladder cancer.

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Interferons

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with binding of interferons and series of complex intracellular reactions take place and with suppression of cell proliferation.