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Flashcards in 05 Alkylating Agents Wolf Deck (15):

What are the general characteristics of Alkylating agents?

Compounds that bind chemically to one of the bases of DNA (usually at the N-7 position of guanine), resulting in single or double strand breaks and cross-linking between the two strands of DNA or between DNA and proteins


What are some examples of Alkylating Agents?

Nitrogen mustards. Mechlorethamine. Chlorambucil. Melphalan. Cyclophosphamide. Ifosfamide. Estramustine


How does Nitrogen Mustard work?

It has two reactive aliphatic -Cl leaving groups which can generate carbonium (C+) or aziridinium ions which will react with unpaired electrons, such as those on the N-7 nitrogen atom of guanine. A second alkylation may then result in interstrand or interstrand cross-linking


For DNA, what are the most reactive nucleophilic sites?

N-7 of guanine > N-3 of adenine > N-1 of adenine > N-1 of cytosine


For Metal complexes, what are the Platinum-containing complexes?

Cisplatin (Platinol). Carboplatin (Paraplatin). Oxaliplatin (Eloxantin). Satraplatin (oral agent, not yet approved)


For Metal complexes, what are the Complexes containing other metals?



What is the QSAR of Platinated Complexes?

Only the cis- complexes are active. The trans complexes are not. The MOA is one of cross-linking, as in the case of the nitrogen mustards. The (NX)2Pt core must be intact for activity


What is the chemistry of Platinated Drugs?

The central Platinum atom in the platinated drugs is coordinated (complexed) and not covalently bound. The 2 chlorine are the leaving ligands, and the amines are the more stably complexed


What is toxicity like with Cisplatin?

The dose-limiting toxicity is Nephrotoxicity, which may be acute or chronic. Cisplatin is one of the most potent emetogenic antineoplastic agents used. Severe nausea/vomiting will occur in all patients not pre-treated with antiemetics


How can the severity of nephropathy from Cisplatin be decreased?

Aggressive normal saline hydration pre- and post-cisplatin and adequate urine output of 100-150ml/hr for 24 hours following cisplatin


What is Nephrotoxicity like with Carboplatin?

Due to the stability, less carboplatin is activated in the renal tubules. Therefore, the incidence of carboplatin-induced nephrotoxicity is much less than with cisplatin


What is Oxaliplatin (Eloxatin)?

A 3rd generation platinum agent. It's MOA is similar to that of the other platinum derivatives, but its spectrum of activity differs from either Cisplatin or Carboplatin. Less nephrotoxic than Cisplatin and less myelotoxic than Carboplatin


What is Oxaliplatin often used for?

Treatment of colorectal cancer that fails to respond to standard chemotherapy


Why is there a difference in the reactivity of Cisplatin with that of Oxaliplatin and Carboplatin?

Because the presence of a chelate ring stabilizes these complexes


What is the conclusion of Alkylating agents?

They are highly reactive chemicals that produce severe chemical modifications in the molecules that regulate cell processes. There is little specificity in targeting