Cancer Chemotherapy:Cancer Chemotherapy:

Development of Drug ResistanceDevelopment of Drug Resistance

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

Resistance MechanismsResistance Mechanisms Induction of thiol containing proteins (metallothioneins) that quench the Induction of thiol containing proteins (metallothioneins) that quench the

alkylators/cross-linkers. (alkylators/cross-linkers. (mechlorethamine, cyclophosphamide, cisplatinmechlorethamine, cyclophosphamide, cisplatin))

Induction of DNA repair enzymes (Induction of DNA repair enzymes (cisplatin, alkylators, bleomycin, any drug that cisplatin, alkylators, bleomycin, any drug that damages DNAdamages DNA))

Induction of glutathione transferase (catalyzes reaction of electrophiles with Induction of glutathione transferase (catalyzes reaction of electrophiles with glutathione (glutathione (alkylatorsalkylators))

Increased enzymatic destruction of drug (Increased enzymatic destruction of drug (bleomycin, cytosine arabinosidebleomycin, cytosine arabinoside))

Increased efflux of drug out of cell mediated by transporters Increased efflux of drug out of cell mediated by transporters (actinomycin D, (actinomycin D, vincristine, vinblastine, etoposide, doxorubicin, paclitaxel)vincristine, vinblastine, etoposide, doxorubicin, paclitaxel)

Overexpression of drug target. Gene amplification of DHFR gives resistance to Overexpression of drug target. Gene amplification of DHFR gives resistance to methotrexatemethotrexate..

Mutation of drug target: Abl-kinase mutations confer resistance to Mutation of drug target: Abl-kinase mutations confer resistance to imatinibimatinib (Gleevec)(Gleevec)

Protein tyrosine kinase inhibitors: Protein tyrosine kinase inhibitors: activating mutations also predict activating mutations also predict

therapeutic successtherapeutic success

Imatinib (Gleevec)Imatinib (Gleevec) specific inhibitor of the Abl, Kit, PDGF-R kinases (active in CML and specific inhibitor of the Abl, Kit, PDGF-R kinases (active in CML and

GIST)GIST) most effective if kinase is playing a dominant role due to activating mutationmost effective if kinase is playing a dominant role due to activating mutation

Gefitinib (Iressa)Gefitinib (Iressa) inhibits Einhibits EGF-R (not effective against the related HER2GF-R (not effective against the related HER2 used in non-small cell lung CAused in non-small cell lung CA success corelates with presence of activating mutations in EGF-R that success corelates with presence of activating mutations in EGF-R that

increase its ligand sensitivityincrease its ligand sensitivity Erlotinib (Tarceva)Erlotinib (Tarceva)

targets EGF-Rtargets EGF-R approved for non-small cell lung CAapproved for non-small cell lung CA effective if tumor is dependent on EGF-Reffective if tumor is dependent on EGF-R

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

Structures of the multi-drug Structures of the multi-drug resistance genesresistance genes

MDR inhibitors may overcome MDR inhibitors may overcome resistance mechanismresistance mechanism

drugs like drugs like verapamil will verapamil will block the multi-block the multi-drug resistance drug resistance pump and could be pump and could be used together with used together with anti-tumor drugsanti-tumor drugs

Toxicities common to many Toxicities common to many cancer chemotherapeutic agentscancer chemotherapeutic agents

1.1. myelosuppression with leukopenia, myelosuppression with leukopenia, thrombocytopenia, and anemiathrombocytopenia, and anemia

2.2. mucous membrane ulcerationmucous membrane ulceration

3.3. alopeciaalopecia

these toxicities are caused by killing of these toxicities are caused by killing of rapidly dividing normal cells in bone marrow rapidly dividing normal cells in bone marrow and epitheliumand epithelium

Duration and extent of bone marrow depression Duration and extent of bone marrow depression depends on drugdepends on drug

AlopeciaAlopecia

Severe:Severe:cyclophosphamidecyclophosphamidedoxorubicindoxorubicinvinblastinevinblastinevincristinevincristine

Moderate:Moderate:etoposideetoposidemethotrexatemethotrexate

Mild:Mild:bleomycinbleomycinfluorouracilfluorouracilhydroxyureahydroxyurea

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

Common Toxicities--continued

Nausea and vomiting: direct action on CNS with somedrugs: e.g. mechlorethamine, cisplatin,cyclophosphamide (delayed by about 8hr)

Extravasation injury: local necrosis with many anti-cancer drugs. e.g. doxorubicin, actinomycin Dvinca alkaloids (vincristine, vinblastine), mechlorethamine (not cyclophosphamide)

Radiation recall: inflammatory reactioncan occur months after radiation exposuredrugs that form free radicals are the probleme.g. actinomycin D, doxorubicin, bleomycin,

Hyperuricemia: caused by rapid tumer lysis and release of purines

Drug-specific toxicitiesDrug-specific toxicities

vincristine: peripheral neurotoxicityvincristine: peripheral neurotoxicity cyclophosphamide: hemorrhagic cystitiscyclophosphamide: hemorrhagic cystitis

due to acrolein metabolite which is nephro and due to acrolein metabolite which is nephro and urotoxic (can be prevented with 2-urotoxic (can be prevented with 2-mercaptoethanesulfonate--mercaptoethanesulfonate--mesnamesna))

doxorubicin: cardiomyopathydoxorubicin: cardiomyopathy bleomycin: pulmonary fibrosis, skin ulcerationbleomycin: pulmonary fibrosis, skin ulceration EGFR inhibitors: skin toxicityEGFR inhibitors: skin toxicity asparaginase: allergic reactionsasparaginase: allergic reactions

Toxicity of Mitotic InhibitorsToxicity of Mitotic Inhibitors

Drug Drug Neurotox Neurotox myelosuppression myelosuppression alopecia alopecia nausea nausea

vinblastinevinblastine rarerare ++++++ ++++ ++ ++vincristinevincristine ++++++ rarerare ++++ rare rarepaclitaxelpaclitaxel ++ ++++++ ++++ mild mild

peripheral neuropathy with vincristine:peripheral neuropathy with vincristine:numbness, weakness, loss of relexes, ataxia, numbness, weakness, loss of relexes, ataxia, cramps, neuritic paincramps, neuritic pain

autonomic neuropathy:autonomic neuropathy:abdominal pain, constipation, urinary retension, abdominal pain, constipation, urinary retension, orthostatic hypotensionorthostatic hypotension

Doxorubicin: cardiac toxicityDoxorubicin: cardiac toxicity Acute: electrocardiogram changes, arrhythmias within Acute: electrocardiogram changes, arrhythmias within

hourshours Chronic: congestive heart failure (not easily treated with Chronic: congestive heart failure (not easily treated with

digitalis)digitalis) changes in mitochondria, sarcoplasmic reticulumchanges in mitochondria, sarcoplasmic reticulum Ca++ATPase activity inhibitedCa++ATPase activity inhibited rapid decrease in CARP (cardiac ankyrin repeat protein)rapid decrease in CARP (cardiac ankyrin repeat protein) slow decrease in heart specific structural proteins and ATP slow decrease in heart specific structural proteins and ATP

generating enzymesgenerating enzymes cellular degeneration observed in ~20% of ptcellular degeneration observed in ~20% of pt decreased left ventricular ejection fraction (more evident while decreased left ventricular ejection fraction (more evident while

exercising)exercising) Risk factors: previous chest radiation, hypertension, Risk factors: previous chest radiation, hypertension,

combination with other cardiotoxic drugs (herceptin)combination with other cardiotoxic drugs (herceptin)

Detecting cardiac Detecting cardiac toxicity in patients toxicity in patients after doxorubicin after doxorubicin

treatmenttreatment

Bleomycin toxicityBleomycin toxicity lungslungs

progressive fibrosis, chronic interstitial inflammationprogressive fibrosis, chronic interstitial inflammation<450mg 3-5% >450mg 10%<450mg 3-5% >450mg 10%

risk factors: age, emphysema, renal failure, previous risk factors: age, emphysema, renal failure, previous radiotherapy to the chest, oxygen administrationradiotherapy to the chest, oxygen administration

skinskin ~50% pts have erythema, peeling, ulceration~50% pts have erythema, peeling, ulceration

systemic toxicity: ~1% of lymphoma pts develop systemic toxicity: ~1% of lymphoma pts develop hyperthermia, hypotension, cardiovascular collapse hyperthermia, hypotension, cardiovascular collapse (release of endogenous pyrogens?)(release of endogenous pyrogens?)

both lungs and skin have low levels of bleomycin both lungs and skin have low levels of bleomycin hydrolase and this may be why they are so sensitive to hydrolase and this may be why they are so sensitive to the drugthe drug

EGFR inhibitors cause skin toxicityEGFR inhibitors cause skin toxicity

Herceptin cardiac toxicityHerceptin cardiac toxicity

Efforts to limit toxicityEfforts to limit toxicity

allopurinol: treat hyperuricemia, uric acid allopurinol: treat hyperuricemia, uric acid precipitates in kidneyprecipitates in kidney

hydration/diuretics: e.g. reduce cisplatin hydration/diuretics: e.g. reduce cisplatin nephrotoxicitynephrotoxicity

leucovorin: limit toxicity of high dose leucovorin: limit toxicity of high dose methotrexatemethotrexate

hematopoietic growth factors: restore bone hematopoietic growth factors: restore bone marrow derived cells (RBCs, lymphocytes, marrow derived cells (RBCs, lymphocytes, granulocytes, platelets)granulocytes, platelets)

Allopurinol inhibits zanthine oxidase and prevents Allopurinol inhibits zanthine oxidase and prevents hyperuricemia during chemotherapyhyperuricemia during chemotherapy

Hematopoietic growth factorsHematopoietic growth factors

erythropoietin: stimulates RBC formationerythropoietin: stimulates RBC formation G-CSF (filgrastim)G-CSF (filgrastim): stimulates neutrophils and : stimulates neutrophils and

eosinophilseosinophils GM-CSF (sargramostim): stimulates neutrophils, GM-CSF (sargramostim): stimulates neutrophils,

monocyte/macrophagemonocyte/macrophage thrombopoietin: stimulates platelet formationthrombopoietin: stimulates platelet formation

benefits: allows high dose chemotherapy with benefits: allows high dose chemotherapy with much less toxicity, reduced risk of infectionmuch less toxicity, reduced risk of infection

Goodman & Gilman

HematopoietiHematopoietic growth c growth factorsfactors