Transcript CC_Resist Tox_07

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)
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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)
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
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 multidrug 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:
cyclophosphamide
doxorubicin
vinblastine
vincristine
Moderate:
etoposide
methotrexate
Mild:
bleomycin
fluorouracil
hydroxyurea
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 anticancer 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 2mercaptoethanesulfonate--mesna)
 doxorubicin: cardiomyopathy
 bleomycin: pulmonary fibrosis, skin ulceration
 EGFR inhibitors: skin toxicity
 asparaginase: allergic reactions
Toxicity of Mitotic Inhibitors
Drug
vinblastine
vincristine
paclitaxel
Neurotox
rare
+++
+
myelosuppression
+++
rare
+++
alopecia
++
++
++
nausea
++
rare
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)
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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 3-5%

>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
Hematopoietic
growth
factors
Goodman & Gilman