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Cyclophosphamide & Chlorambucil
- These are alkylating agents, which bind DNA through alkylating links and cross-links, primarily at the N7 position of guanine.
- We show a bloody bladder to highlight the potential for cyclophosphamide-induced hemorrhagic cystitis.
Mechanism
Alkylation
- The alkylating agents comprise a large group of a variety of drugs that interfere with tumor cell DNA replication by forming links within strands of DNA.
- The N7 position of guanine has the greatest alkylation affinity – it most readily reacts with alkylating agents.
- Alkyl groups are fragments with a vacant attachment site that is highly attractive to a nucleophile, such as the N7 of guanine.
- The alkyl group can form both intrastrand linking within a single strand of DNA or it can form interstrand crosslinking between two strands of DNA.
- These links and crosslinks interfere with further DNA replication/cell division and, thus, further tumor growth.
Hemorrhagic Cystitis
Overview
- Cyclophosphamide can induce hemorrhagic cystitis: hemorrhage from diffuse bladder inflammation; it occurs through various pathological mechanisms.
Acrolein
- As one important component of this pathogenesis, indicate that acrolein is a toxic urinary metabolite of cyclophosphamide that accumulates in the bladder.
MESNA
- In order to prevent acrolein toxicity, we administer MESNA (M-E-S-NA for 2-mercaptoethanesulfonate sodium) as a pre-treatment, so it's on-board when the cyclophosphamide is given as a way to bind up the acrolein; it acts as a sulfhydryl (aka thiol) donor which bonds to and clears acrolein.
- It's important to understand that MESNA doesn't treat the hemorrhagic cystitis, itself (it doesn't help heal the damaged bladder) but rather it acts as a preventative of the damage by neutralizing acrolein.