Cancer Chemotherapy:

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Cancer Chemotherapy

• Development of Drug Resistance

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

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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

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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
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Structures of the multi-drug resistance genes
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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

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Toxicities common to many cancer chemotherapeutic
agents

• myelosuppression with leukopenia,
  thrombocytopenia, and anemia
• mucous membrane ulceration
• alopecia
• these toxicities are caused by killing of rapidly
  dividing normal cells in bone marrow and
  epithelium

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Duration and extent of bone marrow depression
depends on drug
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Alopecia
Severe cyclophosphamide doxorubicin vinblastin
e vincristine Moderate etoposide methotrexate

Mild bleomycin fluorouracil hydroxyurea
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CDK inhibitors applied to scalp prevent alopecia
from etoposide or cyclophosphamide/doxorubicin
combination
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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
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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

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Toxicity of Mitotic Inhibitors
Drug Neurotox myelosuppression
alopecia nausea vinblastine rare
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
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Doxorubicin cardiac toxicity

• Acute electrocardiogram changes, arrhythmias
  within hours
• Chronic congestive heart failure (not easily
  treated with digitalis)
• changes in mitochondria, sarcoplasmic reticulum
• CaATPase 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)

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Detecting cardiac toxicity in patients after
doxorubicin treatment
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Bleomycin toxicity

• lungs
• progressive fibrosis, chronic interstitial
  inflammation
• lt450mg 3-5 gt450mg 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

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EGFR inhibitors cause skin toxicity
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Herceptin cardiac toxicity
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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)

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Allopurinol inhibits zanthine oxidase and
prevents hyperuricemia during chemotherapy
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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

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Hematopoietic growth factors
Goodman Gilman