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Flashcards in AntiNeoplasic Agents Deck (82):
1

cytotoxic agents of chemotherapy

DNA damaging agents

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chemotherapy

nonspecific drugs selected for clinical testing without a known mechanism of action. somehow damages or interferes with the production of DNA.

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rational drug development

identification of a specific biological target and make components that block or stimulate it

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in which phase of the cell cycle do most cancer drugs work?

S phase

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p53 & Rb

tumor suppressor gene (p53) and antagonist. key regulators of the cell cycle. both activated by phosphoryation.

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p53 regulation

phosphorylation prevents cell cycle progression and activates damage repair or apoptosis (via more phosphorylation)

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Rb regulation

phosphorylation activates cell cycle progression. progressive lack of Ps leads to repair or apoptosis

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what makes cancer cells susceptible to chemotherapy?

already have mutations, DNA repair mechanisms are impaired, divide frequently

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chemotherapy side effects

myelosuppression, hair loss, diarrhea, neuropathy. all effects of rapidly cycling normal cells (bone marrow progenitors, intestinal crypt epithelium, hair follicles) and long axons dependent on microtubules

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issues with chemotherapy dosing

need to maximize dose and give it continuously to kill cancer cells, but also need to minimize dose and allow breaks in treatment so as not to kill all normal cells

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which normal cells in body are the most sensitive to chemotherapy?

bone marrow progenitors. if destroyed, must be replaced via bone marrow (stem cell) transplant

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two principal cell kill models

log kill & norton simon hypothesis

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log kill model

cell kill is proportional to tumor mass. follows first order kinetics: each drug dose kills constant percentage of cells. Some will grow back between treatments but progressively go down. need numerous therapies

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norton simon hypothesis

proportion of cells killed is a function of tumor growth rate. easier to kill cells in rapidly growing tumors with just a few cycles of therapy

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what does the likelihood of eradication depend upon?

the initial tumor volume. but then the issue is that clinical detection occurs at a very high number already (10^8)

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log kill model limitations

enormous tumors require sequential treatments, resistance will emerge (tumor heterogeneity), and bc side effects are cumulative, can't keep treating forever

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gompertzian growth

cancer cells don't actually grow in exponential fashion but instead asymptotic bc they eventually run out of food. so repeated cycles of therapy can successfully eradicate them

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dose dense therapy

as tumor gets smaller, it grows faster. so with successive hits of therapy, you can kill higher fraction each time. shorter time between doses is helpful

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intrinsic drug resistance

chemotherapy can't reach the brain and the testes. these tissues are protected by transport constraint. also can be due to high intra-tumoral pressure.

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acquired resistance

multi drug resistance, enhanced dna repair, mutation of drug targets, natural selection within heterogenous clonal population

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mediator of multi drug resistance (MDR)

p-glycoprotein

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p-glycoprotein

ATP dependent pumps that remove drugs from the cell. normally expressed in most cells at low levels, unregulated in cancers exposed to drugs. pump inhibition has been unsuccessful

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4 enzymes that repair damaged DNA

O6-akylguanine-DNA alkyltransferase (AGT), poly(ADP-ribose) polymerase1 (PARP-1), DNA glycolsylase/XCCR1, ERCC1 (cisplatin)

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why are pancreatic tumors so difficult to treat?

create an ultra dense tumor stroma that causes high intra-tumoral pressure and decreases drug penetration

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goldie-coldman hypothesis of drug resistance

drug resistant cells are present in patient at diagnosis. exists prior to exposure via spontaneous mutations in heterogeneous clonal population.

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how can we overcome drug resistance most effectively?

multiple agents should be given simultaneously over the shortest period of time as early in the growth of the cancer as possible and

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principles of combination chemotherapy

all drugs must be active, non-overlapping toxicity, different or synergistic mechanisms of action, different mechanisms of resistance, all given at optimum dose and schedule

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4 broad classes of chemotherapy agents

direct dna damaging agents, inhibitors of chromatin remodeling, inhibitors of dan synthesis, tubulin interactive drugs

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types of direct dna damaging agents

cross linkers, alkylators, intercalators

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cisplatin

directly damages DNA by cross liking it

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mechanism of action of cisplatin

unstable in low intracellular concentrations of Cl--> loses Cl and electrophile binds to DNA, which makes replication difficult. Leads to cell cycle arrest and apoptosis. fast growing cells can't repair the adducts

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mechanisms of resistance to cisplatin

decreased cellular drug uptake, glutathione buffer over expression, enhanced repair of DNA adducts, tolerance of DNA adducts

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alkylating agents

prodrugs that attach alkyl groups to DNA, making it difficult for polymerase to recognize strands. cross link guanine in DNA double helix strands.

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examples of alkylating agents

cyclophosphamide & ifosfamide

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cyclophosphamide & ifosfamide

mustard derivative alkylating agents that are prodrugs activated by liver p450.

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resistance to alkylating drugs

DNA repair enzymes, decreased permeability, over expression of thiols like glutathione

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what phase of cell cycle do direct dna damaging agents affect?

S phase

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inhibitors of chromatin remodeling

topoisomerase 1&2 inhibitors

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Doxorubicin

binds to DNA and results in a complex that topoisomerase 2 can no longer unwind and replication is therefore inhibited.

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topotecan & Irinotecan

bind to the topoisomerase 1/DNA complex to prevent re-ligation of SS breaks.

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topoisomerase activity

relieve torsional strain in DNA by causing reversible single strand breaks

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resistance mechanisms to inhibitors of chromatin remodeling

increase p-glycoprotein, activate non-P-glycoprotein transmembrane pumps, detoxify with glutathione, decrease expression of topoisomerase 1/2, enhance DNA repair, decrease metabolic conversion of active moiety of irinotecan

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phase of cell cycle targeted by chromatin remodeling inhibitors

S phase

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5-FU (5-Fluorouracil)

antimetabolite (uridine analog) that binds to and inhibits thymidylate synthase (TS), so that thymidine cannot be synthesized. arrests cell in s phase

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antimetabolites

structural analogs of naturally occurring substances required for specific biochemical rxns. fraudulently substitute themselves for purines or pryimidines involved in nucleus acid synthesis.

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major antimetabolite drug categories

folate antagonists, pyrimidine analogs, purine analogs.

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resistance to 5-FU

increase rate of TS, reduce affinity of TS for FdUMP, elevate DPD activity (degrades 5-FU)

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methotrexate

folate antagonist that blocks DHFR (folic acid to THF), disrupting pyrimidine synthesis.

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leucovorin (folinic acid)

antidote for methotrexate that preferentially rescues normal tissue over cancerous cells by supplying cell with reduced folate

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mechanism of resistance to methotrexate

decreased cellular transport, cellular drug efflux pumps, decreased polyglutamylation of mtx, increased polyglutamate hydrolases, increase DHFR

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Cytarabine (Ara-C)

pyrimidine nucleoside antimetabolite. causes inefficient DNA synthesis

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resistance to Ara-C

reduced cellular influx, reduced phosphorylation, degradation

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portion of cell cycle affected by antimetabolites

S phase

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what do tubulin interactive drugs prevent

cytokinesis and separation of chromosomes (anti-mitotics)

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microtubule stabilizers

taxanes

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microtubule destabilizers

vincas

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examples of taxanes

paclitaxel, docetaxel, cabazitaxel (TAXEL)

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mechanism of taxanes

stabilize and freeze microtubules in place, preventing depolymerization. causes mitotic block at anaphase, triggers apoptosis

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resistance to taxanes

P-glycoprotein, alter microtubule associated protein binding sites

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examples of vincas

vinblastine, vincristine, vindesine, vinorelbine (VIN)

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mechanism of vincas

prevent the formation of microtubules.

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resistance to vincas

efflux via P-glycoprotein, mutations in tubulin, altered expression of tubulin isoforms

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what stage of cell cycle do vincas/taxanes affect?

M phase

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side effects of alkylating agents, chromatin inhibitors, antimetabolites

cytopenia, neutropenia, thrombocytopenia, diarrhea, hair loss

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side effects of vincas/taxanes

neurotoxicity, neutropenia, hair loss

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what has the main focus/target of rational cancer thus far?

receptor tyrosine kinases

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molecularly targeted therapy

an agent that interacts with a defined molecular target other than DNA and negatively affects cell survival or growth. KNOWN MECHANISM OF ACTION

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how are monoclonal antibodies administered?

IV

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how is small molecule therapy administered?

Orally

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angiogenic switch

small tumors acquire the ability to stimulate angiogenesis by up regulating VEGF and thereby acquiring access to blood supply, facilitating growth and metastasis

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bevacizumab (Avastin)

monoclonal antibody that removes VEGF from circulation to prevent neovascularization and inhibits tumor growth

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HIF1a

stimulatory TF of VEGF. no inhibitory drugs yet

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ways to block VEGF

Avastin and through inhibition of tyrosine kinase domain

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imatinib mesylate

ATP mimetic/competitive inhibitor that binds kinase domains better than ATP and therefore prevents downstream signaling. works against KIT, Bcr-Abl, & PDGFRA/B

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side effects of imatinib

edema, diarrhea, white hair

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Erlotinib

epidermal GF receptor (EGFR) tyrosine kinase inhibitor. blocks downstream signaling. induces G1 cell cycle arrest and angiogenesis.

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side effects of erlotinib

follicular rash, diarrhea, weird hair

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antibody vs TKI (tyrosine kinase inhibitors)

Abs block ligand binding, TKIs block downstream signaling.

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HER2

signals cells to divide

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trastuzumab (herceptin)

targets HER2 (GF receptor protein). used to treat breast cancer

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problem with alkylating agents

they are cytotoxic, mutagenic, and carcinogenic--> therefore they can actually cause secondary cancers

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dose of targeted agents

continuous