1. Alkylating agents 2. Antitumor antibiotics

Exam 50- Antineoplastic Flashcards by Sarah Fodor

tumor initiation and progression

genetic mutation leads to abnormal proliferation
more mutations occur within cells
advantageous mutations are selected so tumor becomes increasing malignant

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___ cells before cancer is identified

10 billion

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adverse affects of antineoplastic drugs to blood

anemia (low RBC)
thrombocytopenia (low platelet)
leukopenia (low WBC)

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adverse affects of antioplastic drugs to the GI

nausea
vomiting
diarrhea
anorexia
mucositis

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other advers affects of antioplastic drugs

opportunistic infections
alopecia (hair cells)
teratogenesis
secondary cancers

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rationale for combined therapy

decreased resistance
increase tolerability
increase efficacy

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combination therapy combines drugs with different:

MOA
cell cycle phase activity
dose-limiting toxicity

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Hodgkin’s Lymphoma combination therapy

ABVD
A=doxorubicin (G2)
B=bleomycin (G2)
V=vinblasine (M)
D=dacbazine (G1 and S)

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G1 phase

prep for DNA replicatin

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S phase

DNA replication

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G2 phase

prep for mitotis

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M phase

=Mitosis

separate of daughter chromosomes and cell division

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Check points of Cell Cycle

DNA damage checkpoint- in G1
- detects damage before entering S as DNA’s being synthesized
Spindle checkpoints - in M
detect any failure of spindle fibers to form properly

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Phase specific drugs general

most active at a particular phase of the cell cycle
time dependent!!
more effective against tumors exhibiting log growth pattern

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phase non-specific drugs

exert toxic effects on cell during cycle, but not a specific part
effective in both high and low growth fraction tumors
concentration dependent!! ∴ give highest dose tolerable

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DNA Damaging Agents

Alkylating agents

2. Antitumor antibiotics

alkylating agnets

dacarbazine

covalently couples alkyl groups to nucleophillic sites on DNA =APOPTOSIS
phase non-specific although peak at late G1 and S phases
mutagenic, carcinogenic

antitumor antibiotics

phase-nonspecivic: although cell is arrested in G2
doxorubicin
-binds to and inhibits DNA function
bleomycin
-binds to DNA and causes free radicals

doxorubicin MOA

binds to DNA and prevents strand passage and relegation (joining) by topoisomerase II

bleomycin MOA

binds to DNA and chelates Fe
-accumulates free radicals

also causes pulmonary fibrosis

Microtubule function inhibitors

vinca alkaloids
(and taxanes)

M phase specific

vinca alkaloids

vinblasitne

bind to alpha and beta tubulin
prevents spindle formation and leads to an inability of cells to secrete chromosomes and cell death

Inhibitors of DNA Synthesis (types)

folate synthesis inhibitors
antimetabolites
topoisomerase inhibitors

Phase S specific

antimetabolites

purine antagonists
=thioguanine
pyrimidine antagoinsts

MOA= insert into DNA and cause
chain termination
strand breakage
inhibition of cell growth

phase S

folate analogues

methotrexate - inhibits dihydrofolate reductase - this enzyme converts dihydrofolate to tetrahydrofolate and eventually into purines treatment= lethal dose of methotrexate followed by foiling acid -rescues cells less dependent on purine synthesis S phase

topoisomerase inhibitors

topotecan - S phase specific - inhibits topoisomerase I active in S phase

topoisomerase I

unravels DNA helix for replication

primary resistance to chemotherapy

1. mutations of p53 - enzyme that shunts to apoptosis, if mutated won't catch alkylation 2. compromised mismatch repair enzyme family - enzymes that repair problems with nicked strands, mismatched DNA or chain termination are compromised os they don't send cell to programmed cell death

acquired resistance to chemotherapy

due to drug use, not inherent to cancer 1. resistance to specific drug -reduced drug uptake, or drug deactivation 2. broad resistance to many drugs =increased MDR1 expression -codes a cell surface protein that enhances drug efflux form cell

bevacizumab

- antiangiogenic - inhibit tumor blood vessel growth - targets vascular endothelial GF - monoclonal antibody ∴ immunotherapy

tamoxifen

=Selective Estrogen Receptor Modulator (SERM) 1. antagonist to ER in breast =inhibits growth-promoting proteins ∴ breast cancer 2. partial agonist to ER in endometrium =increases risk for endometrial cancer

Hep B cancer

=DNA virus | associated with liver cancer

HPV cancer

=DNA virus | associated with cervical cancer

Herpesviruses cancer

=DNA Virus associated with Burkitt's lymphoma Kaposi's sarcoma nasopharyngeal carcinoma

Hep C cancer

=RNA virus | associated with liver

Retrovirus cancer

=RNA virus | associated with adult T-cell leukemia

Gardasil

prevents infection from HPV types 6, 11, 16, and 18 16 and 18 -> cervical cancer 6 and 11 -> genital warts

oncogenes

genes that promote cell proliferation and inhibit programmed cell death -if mutated or over expressed = mitosis normal cells require growth factors, but mutations result in growth factor independence

imatinib

=Kinase inhibitor BCR-ABL gene => fusion protein (continuously active kinase) -imatinib = 50-95% of puts with chronic myeloid tumor