Potentiation of RSU-1069 tumour cytotoxicity by 5-hydroxytryptamine (5-HT).
It is known that many solid animal tumours have a lower oxygenation level than most normal tissues and, in addition, that this level of oxygenation can be further decreased by systemic administration of 5-hydroxytryptamine (5-HT). The present study has investigated if such selective decrease in tumour oxygenation can be exploited by using the hypoxic cell cytotoxin, RSU-1069. The results obtained show that 5-HT at a dose of 5 mg kg-1, although not cytotoxic alone, can potentiate the cytotoxic effects of RSU-1069 in the Lewis lung carcinoma over the dose range 0.01-0.15 mg g-1. Maximum potentiation occurs when 5-HT is administered after RSU-1069. Potentiation of RSU-1069 cytotoxicity was observed using both the soft agar excision assay as an endpoint as well as in situ growth delay. In addition, the study shows that potentiation of RSU-1069 (0.1 mg g-1) cytotoxicity can be seen with 5-HT doses as low as 0.5 mg kg-1. In contrast to the tumour cytotoxicity results, 5-HT at a dose of 5 mg kg-1 i.p. did not affect the systemic toxicity, as measured by LD50/7d of RSU-1069. Thus, these results indicate that 5-HT can increase the therapeutic efficiency of RSU-1069. Such a finding is consistent with the rationale that selective reduction in tumour blood flow and oxygenation induced by 5-HT can be exploited using the hypoxic cell cytotoxin RSU-1069.
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D008175:Lung Neoplasms / Q000188:drug therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D008920:Misonidazole / Q000031:analogs & derivatives* / Q000627:therapeutic use; D012701:Serotonin / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D012701:Serotonin; C041712:1-(2-nitro-1-imidazolyl)-3-aziridino-2-propanol; D008920:Misonidazole