Flashcards in AntiNeoplasic Agents Deck (82):
cytotoxic agents of chemotherapy
DNA damaging agents
nonspecific drugs selected for clinical testing without a known mechanism of action. somehow damages or interferes with the production of DNA.
rational drug development
identification of a specific biological target and make components that block or stimulate it
in which phase of the cell cycle do most cancer drugs work?
p53 & Rb
tumor suppressor gene (p53) and antagonist. key regulators of the cell cycle. both activated by phosphoryation.
phosphorylation prevents cell cycle progression and activates damage repair or apoptosis (via more phosphorylation)
phosphorylation activates cell cycle progression. progressive lack of Ps leads to repair or apoptosis
what makes cancer cells susceptible to chemotherapy?
already have mutations, DNA repair mechanisms are impaired, divide frequently
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
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
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
two principal cell kill models
log kill & norton simon hypothesis
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
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
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)
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
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
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
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.
multi drug resistance, enhanced dna repair, mutation of drug targets, natural selection within heterogenous clonal population
mediator of multi drug resistance (MDR)
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
4 enzymes that repair damaged DNA
O6-akylguanine-DNA alkyltransferase (AGT), poly(ADP-ribose) polymerase1 (PARP-1), DNA glycolsylase/XCCR1, ERCC1 (cisplatin)
why are pancreatic tumors so difficult to treat?
create an ultra dense tumor stroma that causes high intra-tumoral pressure and decreases drug penetration
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.
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
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
4 broad classes of chemotherapy agents
direct dna damaging agents, inhibitors of chromatin remodeling, inhibitors of dan synthesis, tubulin interactive drugs
types of direct dna damaging agents
cross linkers, alkylators, intercalators
directly damages DNA by cross liking it
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
mechanisms of resistance to cisplatin
decreased cellular drug uptake, glutathione buffer over expression, enhanced repair of DNA adducts, tolerance of DNA adducts
prodrugs that attach alkyl groups to DNA, making it difficult for polymerase to recognize strands. cross link guanine in DNA double helix strands.
examples of alkylating agents
cyclophosphamide & ifosfamide
cyclophosphamide & ifosfamide
mustard derivative alkylating agents that are prodrugs activated by liver p450.
resistance to alkylating drugs
DNA repair enzymes, decreased permeability, over expression of thiols like glutathione
what phase of cell cycle do direct dna damaging agents affect?
inhibitors of chromatin remodeling
topoisomerase 1&2 inhibitors
binds to DNA and results in a complex that topoisomerase 2 can no longer unwind and replication is therefore inhibited.
topotecan & Irinotecan
bind to the topoisomerase 1/DNA complex to prevent re-ligation of SS breaks.
relieve torsional strain in DNA by causing reversible single strand breaks
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
phase of cell cycle targeted by chromatin remodeling inhibitors
antimetabolite (uridine analog) that binds to and inhibits thymidylate synthase (TS), so that thymidine cannot be synthesized. arrests cell in s phase
structural analogs of naturally occurring substances required for specific biochemical rxns. fraudulently substitute themselves for purines or pryimidines involved in nucleus acid synthesis.
major antimetabolite drug categories
folate antagonists, pyrimidine analogs, purine analogs.
resistance to 5-FU
increase rate of TS, reduce affinity of TS for FdUMP, elevate DPD activity (degrades 5-FU)
folate antagonist that blocks DHFR (folic acid to THF), disrupting pyrimidine synthesis.
leucovorin (folinic acid)
antidote for methotrexate that preferentially rescues normal tissue over cancerous cells by supplying cell with reduced folate
mechanism of resistance to methotrexate
decreased cellular transport, cellular drug efflux pumps, decreased polyglutamylation of mtx, increased polyglutamate hydrolases, increase DHFR
pyrimidine nucleoside antimetabolite. causes inefficient DNA synthesis
resistance to Ara-C
reduced cellular influx, reduced phosphorylation, degradation
portion of cell cycle affected by antimetabolites
what do tubulin interactive drugs prevent
cytokinesis and separation of chromosomes (anti-mitotics)
examples of taxanes
paclitaxel, docetaxel, cabazitaxel (TAXEL)
mechanism of taxanes
stabilize and freeze microtubules in place, preventing depolymerization. causes mitotic block at anaphase, triggers apoptosis
resistance to taxanes
P-glycoprotein, alter microtubule associated protein binding sites
examples of vincas
vinblastine, vincristine, vindesine, vinorelbine (VIN)
mechanism of vincas
prevent the formation of microtubules.
resistance to vincas
efflux via P-glycoprotein, mutations in tubulin, altered expression of tubulin isoforms
what stage of cell cycle do vincas/taxanes affect?
side effects of alkylating agents, chromatin inhibitors, antimetabolites
cytopenia, neutropenia, thrombocytopenia, diarrhea, hair loss
side effects of vincas/taxanes
neurotoxicity, neutropenia, hair loss
what has the main focus/target of rational cancer thus far?
receptor tyrosine kinases
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
how are monoclonal antibodies administered?
how is small molecule therapy administered?
small tumors acquire the ability to stimulate angiogenesis by up regulating VEGF and thereby acquiring access to blood supply, facilitating growth and metastasis
monoclonal antibody that removes VEGF from circulation to prevent neovascularization and inhibits tumor growth
stimulatory TF of VEGF. no inhibitory drugs yet
ways to block VEGF
Avastin and through inhibition of tyrosine kinase domain
ATP mimetic/competitive inhibitor that binds kinase domains better than ATP and therefore prevents downstream signaling. works against KIT, Bcr-Abl, & PDGFRA/B
side effects of imatinib
edema, diarrhea, white hair
epidermal GF receptor (EGFR) tyrosine kinase inhibitor. blocks downstream signaling. induces G1 cell cycle arrest and angiogenesis.
side effects of erlotinib
follicular rash, diarrhea, weird hair
antibody vs TKI (tyrosine kinase inhibitors)
Abs block ligand binding, TKIs block downstream signaling.
signals cells to divide
targets HER2 (GF receptor protein). used to treat breast cancer
problem with alkylating agents
they are cytotoxic, mutagenic, and carcinogenic--> therefore they can actually cause secondary cancers