Cancer Chemotherapy: Development of Drug Resistance

Probability that all tumor cells will be sensitive to a drug as a function of size of the tumor

Resistance Mechanisms  Induction of thiol containing proteins (metallothioneins) that quench the alkylators/cross-linkers. (mechlorethamine, cyclophosphamide, cisplatin)  Induction of DNA repair enzymes (cisplatin, alkylators, bleomycin, any drug that damages DNA)  Induction of glutathione transferase (catalyzes reaction of electrophiles with glutathione (alkylators)  Increased enzymatic destruction of drug (bleomycin, cytosine arabinoside)  Increased efflux of drug out of cell mediated by transporters (actinomycin D, vincristine, vinblastine, etoposide, doxorubicin, paclitaxel)  Overexpression of drug target. Gene amplification of DHFR gives resistance to methotrexate.  Mutation of drug target: Abl-kinase mutations confer resistance to imatinib (Gleevec)

Protein tyrosine kinase inhibitors: activating mutations also predict therapeutic success  Imatinib (Gleevec)  specific inhibitor of the Abl, Kit, PDGF-R kinases (active in CML and GIST)  most effective if kinase is playing a dominant role due to activating mutation  Gefitinib (Iressa)  inhibits EGF-R (not effective against the related HER2  used in non-small cell lung CA  success corelates with presence of activating mutations in EGF-R that increase its ligand sensitivity  Erlotinib (Tarceva)  targets EGF-R  approved for non-small cell lung CA  effective if tumor is dependent on EGF-R

MULTIDRUG RESISTANCE IN CANCER Three decades of multidrug-resistance research have identified a myriad of ways in which cancer cells can elude chemotherapy, and it has become apparent that resistance exists against every effective drug, even our newest agents. Michael M. Gottesman

Structures of the multi-drug resistance genes

MDR inhibitors may overcome resistance mechanism  drugs like verapamil will block the multi- drug resistance pump and could be used together with anti-tumor drugs

Toxicities common to many cancer chemotherapeutic agents 1.myelosuppression with leukopenia, thrombocytopenia, and anemia 2.mucous membrane ulceration 3.alopecia  these toxicities are caused by killing of rapidly dividing normal cells in bone marrow and epithelium

Duration and extent of bone marrow depression depends on drug

Alopecia Severe:cyclophosphamidedoxorubicinvinblastinevincristineModerate:etoposidemethotrexate Mild:bleomycinfluorouracilhydroxyurea

CDK inhibitors applied to scalp prevent alopecia from etoposide or cyclophosphamide/doxorubicin combination

Common Toxicities--continued Nausea and vomiting: direct action on CNS with some drugs: e.g. mechlorethamine, cisplatin, cyclophosphamide (delayed by about 8hr) Extravasation injury: local necrosis with many anti- cancer drugs. e.g. doxorubicin, actinomycin D vinca alkaloids (vincristine, vinblastine), mechlorethamine (not cyclophosphamide) Radiation recall: inflammatory reaction can occur months after radiation exposure drugs that form free radicals are the problem e.g. actinomycin D, doxorubicin, bleomycin, Hyperuricemia: caused by rapid tumer lysis and release of purines

Drug-specific toxicities  vincristine: peripheral neurotoxicity  cyclophosphamide: hemorrhagic cystitis  due to acrolein metabolite which is nephro and urotoxic (can be prevented with 2- mercaptoethanesulfonate--mesna)  doxorubicin: cardiomyopathy  bleomycin: pulmonary fibrosis, skin ulceration  EGFR inhibitors: skin toxicity  asparaginase: allergic reactions

Toxicity of Mitotic Inhibitors Drug Neurotox myelosuppression alopecia nausea vinblastinerare vincristine+++rare++ rare paclitaxel mild peripheral neuropathy with vincristine: numbness, weakness, loss of relexes, ataxia, cramps, neuritic pain autonomic neuropathy: abdominal pain, constipation, urinary retension, orthostatic hypotension

Doxorubicin: cardiac toxicity  Acute: electrocardiogram changes, arrhythmias within hours  Chronic: congestive heart failure (not easily treated with digitalis)  changes in mitochondria, sarcoplasmic reticulum  Ca++ATPase activity inhibited  rapid decrease in CARP (cardiac ankyrin repeat protein)  slow decrease in heart specific structural proteins and ATP generating enzymes  cellular degeneration observed in ~20% of pt  decreased left ventricular ejection fraction (more evident while exercising)  Risk factors: previous chest radiation, hypertension, combination with other cardiotoxic drugs (herceptin)

Detecting cardiac toxicity in patients after doxorubicin treatment

Bleomycin toxicity  lungs  progressive fibrosis, chronic interstitial inflammation  450mg 10%  risk factors: age, emphysema, renal failure, previous radiotherapy to the chest, oxygen administration  skin  ~50% pts have erythema, peeling, ulceration  systemic toxicity: ~1% of lymphoma pts develop hyperthermia, hypotension, cardiovascular collapse (release of endogenous pyrogens?)  both lungs and skin have low levels of bleomycin hydrolase and this may be why they are so sensitive to the drug

EGFR inhibitors cause skin toxicity

Herceptin cardiac toxicity

Efforts to limit toxicity  allopurinol: treat hyperuricemia, uric acid precipitates in kidney  hydration/diuretics: e.g. reduce cisplatin nephrotoxicity  leucovorin: limit toxicity of high dose methotrexate  hematopoietic growth factors: restore bone marrow derived cells (RBCs, lymphocytes, granulocytes, platelets)

Allopurinol inhibits zanthine oxidase and prevents hyperuricemia during chemotherapy

Hematopoietic growth factors  erythropoietin: stimulates RBC formation  G-CSF (filgrastim): stimulates neutrophils and eosinophils  GM-CSF (sargramostim): stimulates neutrophils, monocyte/macrophage  thrombopoietin: stimulates platelet formation  benefits: allows high dose chemotherapy with much less toxicity, reduced risk of infection

Goodman & Gilman Hematopoietic growth factors