Therapeutic evaluation of five nitrosoureas in a human melanoma xenograft system.
The development of nitrosoureas has switched from more lipophilic derivatives to congeners with higher water-solubility, since this property was presumably associated with a decrease in myelosuppression. We have compared the therapeutic efficacy of clinically well-known lipophilic nitrosoureas BCNU, CCNU, and MeCCNU with the recently introduced water-soluble nitrosoureas chlorozotocin (CZT) and hydroxyethyl-CNU (HeCNU), using a human melanoma xenograft system. There were considerable differences in tumor-inhibitory activity, with HeCNU ranking first and CZT last, and the rank order was similar for drug-induced lethality or bone marrow damage (in terms of reduced cellularity or macromolecular DNA damage). When the doses are expressed as percentages of the corresponding LD10/30 values, CZT ranks last and HeCNU low among conventional nitrosoureas. We conclude that water-solubility is not associated with reduced myelosuppression and that other guidelines will have to be adopted for rational development of nitrosoureas.
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy*; D002330:Carmustine / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008130:Lomustine / Q000627:therapeutic use; D008297:Male; D008545:Melanoma / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009607:Nitrosourea Compounds / Q000627:therapeutic use*; D012673:Semustine / Q000627:therapeutic use; D013311:Streptozocin / Q000031:analogs & derivatives / Q000627:therapeutic use; D014181:Transplantation Immunology / Q000187:drug effects; D014183:Transplantation, Heterologous
D009607:Nitrosourea Compounds; D012673:Semustine; C007028:chlorozotocin; D013311:Streptozocin; D008130:Lomustine; C013876:elmustine; D002330:Carmustine