cytotoxic drugs

Question 1

cells most likely to metastasize?

Answer 1

Epithelial = Carcinoma (85%) Squamous – surface (skin) Adenomatous – glandular (breast) Transitional – layered (bladder) Blood/Lymph = Leukaemia/Lymphoma (7%) Connective Tissue = Sarcoma (1%) Bone, Cartilage, Muscle Brain = Glioma (1%)

Question 2

angiogenic potential?

Answer 2

add pic

Question 3

Gompertzian Growth

Answer 3

a pattern of cell growth in tumors in which there is increased doubling time and decreased growth fraction as a function of time

Question 4

growth fraction?

Answer 4

Growth Fraction: The proportion of cells in a tumor that is proliferating in relation to the total number of cells in the tumor

Question 5

log kill hypothesis?

Answer 5

A drug or drug combination can kill a constant fraction of cancer cells. Certain cells survive each treatment by chance alone and are sensitive to subsequent treatments.

Question 6

affects of specific and non specific phase chemo agents?

Answer 6

For noncycledependent agents, such as irradiation or alkylating agents, increasing dose produces increasing cell kill. For cyclespecific agents, such as antimetabolites, which kill only actively growing cells, increasing doses have a plateau effect as cell growth slows with chemotherapy. Prolonging the duration of exposure to antimetabolites will increase the cell kill

Question 7

cytotoxicity is?

Answer 7

area undr the curve

Question 8

combo therapies must?

Answer 8

be highly effective as single agents (high fraction of complete response) • have individual mechanisms of action • have non-overlapping toxicity they are good because , Increases maximum cell kill and decreases toxicity •Kills cells in tumours with heterogeneous cell populations •Reduces the chances of development of resistant clones

Question 9

major cytotoxic drug groups?

Answer 9

Alkylating agents eg cyclophosphamide, cisplatin procarbazine - form covalent bonds with DNA and impede replication •Anti-metabolites (methotrexate, 5-FU, gemcitabine) - block or subvert metabolic pathways involved in DNA synthesis •Cytotoxic antibiotics (anthracyclines eg doxorubicin) - bind DNA to halt transcription, also TOPO II inhibitor •Plant derivatives (vinca alkaloids, taxanes) - effect microtubule function to inhibit mitosis •Miscellaneous agents - Topoisomerase (TOPO) inhibitors (etoposide, campothecins) - inhibit TOPO I/II and thus DNA replication - indirect DNA damaging agents (bleomycin, mitomycin c) - generate free radicals which promote DNA strand breakage

Question 10

mechanisms pf cytotoxic drugs?

Answer 10

Alkylating agents eg cyclophosphamide, cisplatin procarbazine - form covalent bonds with DNA and impede replication •Anti-metabolites (methotrexate, 5-FU, gemcitabine) - block or subvert metabolic pathways involved in DNA synthesis •Cytotoxic antibiotics (anthracyclines eg doxorubicin) - bind DNA to halt transcription, also TOPO II inhibitor •Plant derivatives (vinca alkaloids, taxanes) - effect microtubule function to inhibit mitosis •Miscellaneous agents - Topoisomerase (TOPO) inhibitors (etoposide, campothecins) - inhibit TOPO I/II and thus DNA replication - indirect DNA damaging agents (bleomycin, mitomycin c) - generate free radicals which promote DNA strand breakage

Question 11

side effects?

Answer 11

Bone Marrow •Leucopenia, Lymphocytopenia, thrombocytopenia, anaemia •Immunosupression •Increased risk of infection •Increased risk of bleeding •Digestive Tract •Ulceration •Hair Roots •Alopecia Affects Tissues with high growth fractions Dose-related •Gonads •Sterility •Tissues undergoing repair •Slow or absent healing •Foetus •Malformation, Abortion

Question 12

drug specific side effects?

Answer 12

CNS Stimulation –Alkylating agents, Steroids •Liver Fibrosis –Methotrexate •Heart (Fibrosis) –Daunomycin •Lung Fibrosis –Bleomycin Not Related to Growth Fraction But still dose-Related

Question 13

late complications of therapeutics?

Answer 13

Leukemogenesis/ myelodysplasia •Testicular and ovarian failure •Relapse/Secondary cancers

Question 14

the goldie-coldman hypothesis?

Answer 14

For an intrinsic rate of mutation to drug resistance, the chances of drug failure (incurability) increase with size of the tumour (105 to 10 8 indicate mutation rate per cell division, i.e. 105 is one mutation per 100000 divisions)

Question 15

drug resistant mechanisms?

Answer 15

Abnormal transport • Decreased cellular retention • Increased cellular inactivation (binding/metabolism) • Altered target protein • Enhanced repair of DNA damage • Altered processing

Question 16

future drugs?

Answer 16

Anti-hormones in breast and prostate cancer –tamoxifen, aromatase inhibitors, LHRH agonists, flutamide •Anti-growth factor therapies for multiple cancer types –tyrosine kinase inhibitors (imatinib, lapatinib) –monoclonal antibodies (trastuzumab [Herceptin], cetuximab) gleevec against oncogenes bcr-abl