23. New Cancer Drugs, Resistance PHARM Flashcards
why do many cancer drugs cause problems with a pt’s normal cells?
many target all rapidly dividing cells and there are toxic to gut lining, bone marrow, and hair follicles.
how are we hoping to avoid systemic toxicities of cancer drugs?
by selecting molecular targets that are specific to the cancer cells (oncogenes or tumor suppressors)
what is the oncogene that is characteristic of CML? what is the drug that targets it?
CML: the BCR-ABL translocation. drug = imatinib
what is the oncogene in non-small cell lung cancer? what drug targets it?
epidermal growth factor receptor (EGFR) overexpression. drug = erlotinib (& others)
what is the oncogene in breast cancer? what drug targets it
Her2/neu overexpression. drug = trastuzumab
what are tumor suppressor genes?
normal genes which are lost or altered and therefore cause malignancy.
examples of tumor suppressor types/genes?
- point mutations (p53, BRCA)
- chromo/DNA deletion
- gene silencing
what kind of mutation is an oncogene?
gain of function mutation, leading to overexpression and tumorigenesis
imatinib: mechanism?
inhibits the tyrosine kinase domain of the BCR-ABL oncoprotein. blocks phosphorylation of downstream proteins
imatinib: effectiveness in CML patients?
can be used in both chronic and blast phase as a single agent. complete remission can occur.
what is imatinib also used for?
treating gastrointestinal stromal tumors (GIST) which overexpress the c-kit tyrosine kinase receptor
imatinib: kinetics? adverse effects? interactions?
orally well absorbed, hepatic (CYP3A4) metabolism
cardiac toxicity
interactions with CYP inhibitors
trastuzumab: what does it do?
recognizes the Her2/neu receptor, blocks it so that growth factor cannot bind.
what cancers is the her2/neu receptor expressed in?
over-expressed in some breast cancers. poor prognosis.
drugs that end in -MAB: what are they likely to be?
monoclonal antibodies
trastuzumab: when is it used alone? what if it is combined with chemo?
- single agent activity in advanced, estrogen-resistant breast cancers.
- when combined with chemo, enhanced clinical responses are observed
Trastuzumab: class?
anti-Her2/neu antibody
trastuzumab: action?
blocks action of Her2/neu receptor in breast cancer.
trastuzumab: adverse effects?
cardiac toxicity, dyspnea, allergic reactions
erlotinib: what pathway does it block?
the EGFR pathway: ligand-activated, works through a series of phosphorylations
what patients are ideal for erlotinib?
lung cancer patients: a subset have an activating mutation of EGFR and are sensitized to EGFR inhibitors
what can happen to EGFR despite treatment with erlotinib?
further mutation and molecular resistance, elevated signaling through alternate pathways
erlotinib: what cancers is it active against?
lung, pancreatic.
erlotinib: what class?
small molecule epidermal growth factor receptor inhibitor
erlotinib: kinetics?
hepatic (CYP3A4) metabolism
erlotinib: adverse effects?
rash, diarrhea, dyspnea
erlotinib: interactions?
smoking, CYP3A4 inhibitors
what is angiogenesis?
formation of new blood vessels by a cancer that promotes tumor cell growth
what are some angiogenic factors?
bFGF, EGF, PDGF
what can inhibit those angiogenic factors?
anti-VEGF, endostatin, angiostatin
why are anti-angiogenic factors so promising?
- resistance is infrequent
- activity does not depend on targeting tumor cells
- chronic therapy could prevent vascularization of tumors
bevacizumab: what class?
anti-angiogenic (anti-vascular endothelial growth factor antibody)
bevacizumab: mechanism?
recognizes vascular endothelial growth factor (VEGF) and blocks its angiogenic activity
bevacizumab: what cancers does it treat?
colon, lung. also useful in macular degeneration and retinal diseases
bevacizumab: complications?
possibility for bleeding, allergic reactions, less wound healing, GI perforation
what is the major difference between normal and tumor cells?
tumor cells are genetically unstable, which allows some cells to escape chemo by mutating.
what is intrinsic resistance?
when a tumor displays resistance to chemo from the onset of treatment.
what is acquired resistance?
when the tumor is initially sensitive, but then commences regrowth despite ongoing treatment
what are some mechanisms of acquired resistance?
- oncogene mutation
- oncogene amplification
- increased metabolism
- decreased drug concentration
- alternative signaling pathways
- stem cell quiescence
- incr plasma protein binding
what are threee types of cancer therapy resistance?
- pharmacokinetic
- cytokinetic
- cellular resistance
describe pharmacokinetic resistance
systemic or tumor mass level resistance.
poor absorption, incr drug clearance, poor tumor vascularity, anatomic sanctuaries (testes, brain)
describe cytokinetic resistance
based on growth rate
tumor is in the wrong phase of cell cycle for specific drug, low growth fraction
describe cellular resistance
changes to tumor cells
gene amplicafication or overexpression, chromo rearrangements, point mutations, changes in chromatin.
–> increased genomic instability
what accounts for multidrug resistance?
some resistance mechanisms are specific to the drug or class of drugs…. in the case of multidrug resistance, cells become resistant to many different classes of agents.
what are ATP-binding cassette transporters?
ABC transporters: transmembrane proteins which pump drugs out of the cell. we are looking for pump blockers to minimize this effect
three examples of ABC transporters?
- P-glycoprotein (PGP)
- multidrug resistance protein (MRP1)
- ABCG2
Overexpression of PGP, MRP1 and ABCG2 causes increased efflux of drugs including what?
vinca alkaloids, antracyclines, taxanes, etoposide, teniposide, camptothecins, imatinib, mitoxantrone
why do we assess for PGP transport activity when developing new drugs?
to screen out drugs that would be inactive in cells that overexpress PGP
what drugs would not be subject to efflux even in the presence of an efflux protein (PGP, MRP1, ABCG2)?
cisplatin, carboplatin, 5-fluorouracil, AraC, cyclophosphamide, bleomycin
describe how decreased expression of topoisomerase II leads to multidrug resistance
DNA agents like doxorubicin and etoposide interact with Topo II. with less of TopoII, there is less substrate for them.
describe how increased repair of DNA leads to multidrug resistance
repair is responsible for resistance to several cancer drugs (esp alkylating agents and cisplatin).
describe how Glutathione-S-transferase induction (GST) leads to multidrug resistance
GST catalyzes conjugation of electrophilic compounds to glutathione. enhances detoxification and elimination. acts on cisplatin, anthracyclines and alkalating agents.
describe how failure to induce apoptosis leads to multidrug resistance
may be due to decreased expression of pro-apoptotic mediators, or increased expression of antiapoptotic mediators. p53 is in here somewhere as well.
describe collateral sensitivity.
way to decrease drug resistance. resistance to one drug causes changes that make the cell MORE sensitive to a second drug
describe combination therapy
way to decrease drug resistance. use of non-cross-resistant drugs (both substrates and non-substrates of ABC transporters)
describe dose escalation
way to decrease drug resistance. used with or without bone marrow transplant
constant infusion, adjuvant therapy: what are these?
ways to decrease drug resistance
Cancer cells isolated from a patient exhibit relative resistance to vincristine, doxorubicin, daunorubicin and etoposide but not to 5-fluorouracil or cisplatin. The mechanism of resistance is most likely to involve what?
overexpression of PGP
Most cases of Chronic Myelogenous Leukemia (CML) are associated with a chromosomal abnormality that can be preferentially targeted using what drug?
imatinib
Attempts to limit tumor growth include inhibiting angiogenesis thus blocking the tumors access to a blood supply. Bevacizumab inhibits the activity of which angiogenic protein?
VEGF
