Pharmacology: Alkylating Agents and Platinum Compounds

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Questions and Answers

What is the unique toxicity of cyclophosphamide and nitrogen mustard?

Neurotoxicity

Severe, persistent vomiting

Ototoxicity

Hemorrhagic cystitis (correct)

What is the primary binding site of cisplatin in DNA?

N7 of adenine

Cytosine

N7 of guanine (correct)

Thymine

What is the major limiting toxicity of cisplatin?

Nephrotoxicity (correct)

Hemorrhagic cystitis

Neurotoxicity

Ototoxicity

What is the mechanism of action of cisplatin?

All of the above Signup and view all the answers

Which of the following platinum compounds has less nephro-, neuro-, and ototoxicity?

Carboplatin Signup and view all the answers

What is the purpose of premedication with antiemetic agents before administering cisplatin?

To prevent severe, persistent vomiting Signup and view all the answers

What is the primary site where cyclophosphamide is biotransformed to hydroxylated intermediates?

Liver Signup and view all the answers

What is the primary strategy to minimize the development of drug resistance in cancer treatment?

Implementing short-term, intensive, intermittent therapy with combinations of drugs Signup and view all the answers

What is the mechanism of cytotoxicity of alkylating agents?

Covalent binding to nucleophilic groups on various cell constituents Signup and view all the answers

What is a potential long-term adverse effect of alkylating agents?

Secondary malignancies such as acute leukemia Signup and view all the answers

Which of the following mechanisms of resistance involves the production of enzymes that repair damaged DNA?

Gene amplification Signup and view all the answers

What is a characteristic of alkylating agents?

They are cell cycle non-specific Signup and view all the answers

What is the primary reason for the toxic manifestations of chemotherapy?

The effect of chemotherapy on normal cells undergoing rapid proliferation Signup and view all the answers

What is the term for the increased efflux of the drug outside the cells, leading to resistance?

Multidrug resistance Signup and view all the answers

What is the consequence of starting leucovorin too early when used with methotrexate?

Reduced toxicity and efficacy of methotrexate Signup and view all the answers

What is the name of the metabolite of cyclophosphamide that reacts with DNA, leading to cytotoxicity?

Phosphoramide mustard Signup and view all the answers

Which of the following is NOT a mechanism of resistance to chemotherapeutic agents?

Increased intracellular drug activation Signup and view all the answers

What is the result of the production of chemically altered enzymes that are no longer recognized by drugs that inhibit unaltered enzymes?

Increased resistance to chemotherapy Signup and view all the answers

Study Notes

Tumor Resistance to Chemotherapy

Tumors can develop resistance to chemotherapy through mutations, especially after prolonged administration of suboptimal drug doses
Short-term, intensive, intermittent therapy with combinations of drugs minimizes the development of drug resistance
Drug combinations are effective against a broader range of resistant cells in the tumor population

Resistance Mechanisms

Enhanced production of enzymes that repair damaged DNA (gene amplification)
Production of chemically altered enzymes that are no longer recognized by drugs (mutations)
Decreased intracellular drug activation
Increased intracellular drug catabolism into inactive metabolites
Reduced uptake of drug into cell
Increased efflux of the drug outside the cells (multidrug resistance)

Chemotherapeutic Agents (Toxicity)

Chemotherapy affects normal cells undergoing rapid proliferation, contributing to toxic manifestations
Cells affected include those of the buccal mucosa, bone marrow, gastrointestinal mucosa, and hair follicles

Alkylating Agents

Nitrogen Mustard: cyclophosphamide
Adverse effects: hemorrhagic cystitis, which can lead to fibrosis of the bladder
Bladder toxicity is attributed to acrolein in the urine
Adequate hydration and IV injection of mesna can minimize bladder toxicity

Platinum Compounds

Cisplatin enters the cell and loses its chlorides, binding to guanine in DNA, forming inter- and intrastrand crosslinks
The resulting cytotoxic lesion inhibits DNA replication and RNA synthesis
Cytotoxicity can occur at any stage of the cell cycle, but cells are most vulnerable in the G1 and S-phases
The primary binding site is the N7 of guanine, but covalent interaction with adenine and cytosine also occurs

Adverse Effects of Platinum Compounds

Severe, persistent vomiting occurs for at least 1 hour after administration of cisplatin and may continue for as long as 5 days
Dose-related nephrotoxicity is a major limiting toxicity, prevented by aggressive hydration
Other toxicities include ototoxicity
Carboplatin has less nephro-, neuro-, and ototoxicity compared to cisplatin

Mechanism of Action of Alkylating Agents

Exert cytotoxic effects by covalently binding to nucleophilic groups on various cell constituents
Alkylation of DNA is probably the crucial cytotoxic reaction that is lethal to tumor cells
Do not discriminate between cycling and resting cells, but are most toxic for rapidly dividing cells
Are mutagenic and carcinogenic, leading to secondary malignancies such as acute leukemia
Are cell cycle non-specific

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Description

Test your knowledge of alkylating agents, including nitrogen mustard and cyclophosphamide, and platinum compounds like cisplatin. Learn about their mechanisms of action and adverse effects, such as hemorrhagic cystitis.