Chemotherapeutic Drugs: Anticancer Agents

Question 1

1. State how the therapeutic index relates to cancer chemotherapy

Answer 1

to achieve tumor control, with limited toxicity, many anti cancer drugs have very small therapeutic window

Question 2

2. Explain the rationale for combination drug therapy.

Answer 2

maximal chance for a cure occurs when multiple agents are given simultaneously, with such a large number of cells, there is a high probability that one or more clones are resistant to any single chemotherapeutic agent

Question 3

3. Describe the basis for cell phase selectivity.

Answer 3

cell cycle-specific drugs act specifically on tumor cells undergoing cycling, and are most effective when a large proportion of tumor cells are proliferating because these drugs disrupt specific parts of the cell cycle

Question 4

6. Identify several mechanisms by which cancer cells develop resistance to cancer chemotherapy.

Answer 4

increased DNA repair
increased inactivation of compound
target or suppressor mutations
decreased activation of prodrugs
decreased drug accumulation

Question 5

7. Describe how genetic influence the efficacy of target- specific anticancer drugs.

Answer 5

.

Question 6

4. Name and describe the mechanisms of action of representative drugs for each class of agents.

Answer 6

DNA-damaging drugs: CCNS drugs, cause

Question 7

5. Describe specific adverse effects and precautions associated with the major anticancer drugs.

Answer 7

immediate toxicities: nausea, vomiting, abdominal pain, anorexia, allergic hypersensitivity, local necrosis due to extravasation
early toxicities: impaired wound healing, myelosuppression, mucosistis, diarrhea and alopecia
delayed toxicitieis
delayed toxicities: aspermia, pulmonary fibrosis and neurotoxicity
late toxicities: sterility, secondary malignancies

Question 8

cyclophosamide

Answer 8

bifunctional akylating agen, forms DNA-DNA protein cross links, admin as a prodrug

possible potentially fatal heart failure and dysrhythmias; hemorrhagic cystitis can be caused by acrolein metabolite, warrents aggressive hydration (MESNA may soak off acrolein)

note liver function important as drug is activated by liver

Question 9

temozolmide

Answer 9

monofuncitonal DNA alkylating agent, methylates DNA, anti-tumor activity correlates best with O6 methylation, admin as a prodrug

used for glioblastomas, astrocytomas and melanosmas due to its good BBB permeability

liver function important

Question 10

carboplatin

Answer 10

reacts with nucleophilic sties to produce inter-stand and intrastrand DNA cross links after oxylate moiety is displaced by water (aquation); GG are particularly active sites

used in many solid tumors

NV (65%) is less sever than with cisplatin, important to admin a antiemetic medication
less neurotoxic, ototoxic and nephrotoxic than cisplatin, thrombocytopenia possible

renal excretion

Question 11

bleomycin

Answer 11

binds to DNA and generate oxygen free radicals from O2 to cause oxidative damage (CCS drug, causes accumulation of cells in the G2 phase

minimally myelo and immunosuppressive, slowly progressing pulmonary toxicity, mucocutaneous reactions, rash and vesiculation, chills and fever

excreted by kidney, important to check for pulmonary damage

Question 12

doxorubicin

Answer 12

intercalates between DNA base pairs, causing helix to change shape thereby inhibiting DNA and RNA polymerases, inhibits topoisomerase II religation, forms superoxide anion and hydroxyl radials that damage cell compenents

all patients develop some cardio toxicity, LVEF should be monitored and drug discontinued with impaired function (toxicity based on cumulative dose 550mg/m2)
red discoloration of urine and sweat as well as vesication (blistering)

Question 13

5-Flurouracil

Answer 13

metabolized to 5dUMP and 5dUMP blocks thymidylate synthase, which is required for conversion of dUMP, decreasing DNA and RNA synthesis, FdUTP becomes incorporated into both DNA and RNA causing chain termination

used in cancers of the colon, rectum, breast, stomach and pancreas

is a CCS drug active in S , dihydropyrimidine dehydrogenase deficiency can enhance 5-FU toxicity

can cause ocular irritation and excessive lacrimation, angina and MI, NVD, ulceration of mouth and HAND-FOOT syndrome as well as myelosuppression

Question 14

gemcitabine

Answer 14

metabolized to nucleotide analogs that inhibit DNA polymerase, cause strand termination and inhibits replication and repair synthesis metabolism

CCS, active in S-phase, toxicity not confined to S phase

is a potent radio sensitizer, not be use with radiotherapy under clinical trial; can cause myelosuppression, flu-like symptoms, hepatotoxicity and hemolytic uremic syndrome (rare)

Question 15

methotrexate

Answer 15

active site inhibitors of DHFR causing depletion of flolates required for nucleotide synthesis, MTX-polyglutamates accumulate and inhibit TS and other enzymes

CCS drug active in S phase,

renal excretion is the primary rout of elimination, including active tubular secretion, NSAIDs reported to reduce tubular secretion of MTX, could enhance toxicity

Steven’s Johnson syndrome, and exfoliative dermatitis, impaired wound healing, myelosuppression, pneumonitis, hepatotoxicity and renal toxicity

Question 16

vincristine

Answer 16

disrupting microtuble assembly, causing cell division to arrest in M phase (CCS)

neurotoxicity manifests in parethesia, tingling that occurs in the stocking and glove pattern, cranial damage, paralysis, ANS dysfunction

limited myelosuppression, reversible alopecia
intrathecal or cisternal admin of vincristine is uniformly fatal

Question 17

paclitaxel

Answer 17

microtubules assembly made extremely stable and nonfunctional, arresting cell in Mphase (CCS)

made from Pacific yew and hepatic metabolism by CYP2C8 and CYP3A4

stocking and glove peripheral neuropathy, myelsuppression, ECG abnormalities and mucositis

pretreat with H1 antagonist, H2 antagonist and a glucocorticoid to reduce likelihood of hypersensitivity reaction; caution with patients with heart or hepatic disease or metastases >2cm in size

Question 18

etoposide

Answer 18

prevents relegation of double-strand breaks induced by topoisomerase II (CCS drug active in S and G2)

used to treat lung, testicular cancers, lymphomas and nonlyohcytic leukemia and Kaposi sarcoma

97% noun to serum albumin so toxicity correlates with hepatic health , 56% excreted in the urine

dose limiting leukopenia, NVD< stomatitis, and reversible alopecia; care with impaired liver or kidney function

Question 19

irinotecan

Answer 19

binds to DNA topoisomerase I leading to single stranded DNA breaks that cause double stranded breaks when meeting replication fork; DNA synthesis is required for cytotoxicity (CCS) admin as a prodrug

metabolized by hepatic CYPs that are induced by anti seizure drugs

dose limiting toxicity, delayed diarrhea with our without neutropenia; can cause exaggerated cholinergic tone and hemorrhagic cystitis

testing advised for UFT A1*28 (phase II metabolism) allele because of increased risk of neutropenia;

Question 20

bevacizumab

Answer 20

binds to VEGF-A prevents VEGF from interacting with the target VEGF receptors (inhibiting angiogenesis)

CCNS drug, suspend admin if proteinuria >2/24hrs, resume when <2g/24h

can result in HTN, increase thromboembolic events, impaired wound healing, GI perforation, pain, nausea, proteinuria, and infusion reaction (flu like)

Question 21

cetuximab

Answer 21

binds to extracellular domain of the human epidermal growth factor receptor (EGFR); induces apoptosis, induces antibody dependent cellular toxicity (CCNS drug)

infusion rx to mouse antigen in 19%, fever, chills, NV, hypotension, angioedema and bronchospasm; acheiform rash, dry skin, fissures, pruritus and exfoliation

monitor for 1hr after infusion for anaphylactic rx

Question 22

rituximab

Answer 22

binds specifically to CD20 a B-lymphocyte antigen, promotes B cell lysis

tx. of relapsed or refractor B cell non-Hodgkin’s lymphoma (HER1R), onset of response takes ~50days

severe or life threatening evens in 57% of patients (CV, GI, renal toxicity), infusion rx to mouse antigen, infections 30% and mucocutaneous reactions, rash, vesiculation and exfoliative dermatitis

all patients should receive diphenhydramine, acetaminophen and possible corticosteroids as premedication

Question 23

trastuzumab

Answer 23

binds to HER2/neu tyrosine kinase receptor to prevent activation, decreases downstream signals, and induces antibody dependent cellular toxicity (CCNS)

used in tx. of solid tumor

possibly fatal ventricular dysfunction and CHF, assess LVEF prior to and during Tx.

Question 24

temsirolimus

Answer 24

binds FKBP and inhibits mTOR, involved in upstream regulation of protein synthesis, cell growth, proliferation and inhibits progression from G1 to S phase of the cell cycle

metabolized to sirolimus (contribute to clinical outcomes) by CYP3A4

can cause dypsnea, pharyngitis, myelosupression, mucositits, metabolic 87%-83% hyperlipidemia, hypertriglyceridemia and edema; rash (47%) pruritus and dry skin), infusion rx. possible

prophylactic diphenhydramine or similar antihistamine before tx.

Question 25

erlotinib

Answer 25

reversible inhibitor of EGFR, binding at ATP binding pocket, preventing autophosphorylation

used for non-small cell lung cancer, pancreatic cancer

metabolized by CYP3A4 (drug interactions possible) most eliminated in feces (liver function important)

rash very common, diarrhea, anorexia and fatigue in over half

caution with liver function- periodic LFT

Question 26

imatinib

Answer 26

targets constitutively active BCR-Abl tyrosine kinase receptor created by the philadelphia chromosome, and targets tyrosine receptor kinases (competitive inhibitor of ATP binding domain)

treats myelogenous leukemia, GI stromal cell tumors, or cancers with certain tyrosine kinase constitutive activity (c-kit, PDGF and other)

metabolized by CYP3A4, azole antifungals can cause significant toxicity

should be taken with food and water to minimize GI distress

Question 27

sunitinib

Answer 27

competitive inhibitor of ATP binding domain in tyrosine kinase, inhibitor of multiple receptor tyrosine kinases, PDGF receptors, VEGF receptors, stem cell factor receptor

metabolized by CYP3A4; HTN, ND, rash or other skin changes, stomatitis, fatigue cardiac dysfunction nd neutropenia

monitor LVEF cardiac function and LFT liver function