DNABinding Drugs

Investigators have conjugated several DNA-binding drugs, including cyclophosphamide,35 l-phenylalanine mustard (melphalan),36 mitomycin C (MMC),37-39 and cis-dichlorodiamminepla-tinum (II) (cisplatin [CDDP])40,41 with PG. Moromoto et al.36 prepared PG-melphalan by coupling the amine group of melphalan with the side-chain carboxyl group of PG in the presence of a water-soluble carbodiimide.36 They investigated the anti-tumor activity of this conjugate in rats bearing sarcoma induced by subcutaneous inoculation of sarcoma cells. The authors used PG-3H-phenyl-alanine as a model compound to demonstrate that free drug could be released from the conjugate and that the conjugate had a tendency to be absorbed through lymphatic routes when compared with free 3H-phenylalanine after subcutaneous administration.36 Roos et al.37 conjugated MMC with PG by using the aziridine amine of MMC.37'38 They found that the release rate, in vitro cytotoxicity, and in vivo anti-tumor activity of PG-MMC conjugates were influenced by the extent of MMC substitution. Furthermore, Seymour et al.42 conjugated MMC with PHEG using an oligopeptide spacer and investigated the effect of this oligopeptide structure on the rate of drug release to optimize the MMC-oligopeptide-PHEG conjugates. The rate of MMC release from the conjugates was affected by the structure of the oligopeptide spacer; spacers bearing a terminal Gly had the fastest release of MMC when compared with other peptide spacers. Another study showed a correlation between the in vitro cytotoxicity of PG-MMC conjugates against B16F10 melanoma and C26 colorectal carcinoma cells and their hydrolytic stability.38 Significant in vivo activity of the conjugates in mice bearing P338 leukemia or C26 colorectal carcinoma seems to result from both the stability of the conjugates in the blood and the rapid drug release, owing to combined chemical and enzymatic hydrolysis.

The clinical use of CDDP is limited by significantly toxic side effects such as acute nephro-toxicity and chronic neurotoxicity and a low therapeutic index. To reduce its toxicity and to maintain prolonged drug activity, investigators complexed CDDP with PG.40,41 They found that PG-CDDP complex (60 mol CDDP/mol PG; molecular weight, 40,000 Da) was more thermo-dynamically stable and has reduced systemic toxicity when compared with CDDP. PG-CDDP was effective in suppressing the growth of OVCAR-3 human ovarian carcinoma in athymic mice and showed a broader therapeutic dose range (80% survival at 3-12 mg/kg) when compared with the narrow, inconsistent effective dose range of free CDDP (80% survival at 1.0-2.5 mg/kg), suggesting that the therapeutic index of CDDP can be improved by complexing it with PG.

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