ABSTRACT
The clastogenic activity of the antineoplastic alkylating agent 3 beta-hydroxy-13 alpha-amino-13,17-seco-5 alpha-androstan-17-oic-13,17-lactam- p-bis (2-chloroethyl) aminophenoxy acetic acid (NSC 294859) and its congeners was studied in human lymphocyte cultures in vitro. Cells were exposed to several concentrations of the drugs for 24 h. It was found that NSC 294859 reduces the mitotic index and causes chromosome- as well as chromatid-type aberrations in a dose-dependent way. From its congeners, the alkylating agent (p-bis(2-chloroethyl)aminophenoxy acetic acid) induces the same phenomena but to a lesser extent, while the modified steroid (3 beta-hydroxy-13 alpha-amino-13,17-seco-5 alpha-androstan-17-oic-13,17-lactam) causes cytogenetic damages at the control level. These results favour the assumption that the antitumour activity of NSC 294859 is mainly based on its cytogenetic effects.
Subject(s)
Antineoplastic Agents/pharmacology , Chromosome Aberrations , Nitrogen Mustard Compounds/pharmacology , Alkylating Agents/pharmacology , Androstanes/pharmacology , Androstanes/toxicity , Antineoplastic Agents/toxicity , Azasteroids/pharmacology , Azasteroids/toxicity , Cell Division/drug effects , Cells, Cultured , DNA Damage , Dose-Response Relationship, Drug , Humans , Lymphocytes/drug effects , Mitotic Index , Nitrogen Mustard Compounds/toxicity , Regression AnalysisABSTRACT
3 beta-Hydroxy-13 alpha-amino-13,17-seco-5 alpha-androstan-17-oic-13,17-lactam-p-bis(2-chloroethyl) aminophenoxyacetate (NSC 294859) is a new modified steroidal alkylating agent. This compound was given by i.p. administration to mice bearing different types of tumour. It was found to exhibit good activity in L1210 and P388 leukaemias with maintenance of activity against advanced tumours. The treatment of colon 26 tumour and B16 melanoma resulted in positive antineoplastic activity. The drug was not shown to be active in a melphalan-resistant P388 line. In this study, NSC 294859 was found to be effective in causing statistically significant increases in sister-chromatid exchange (SCE) rates and cell division delays. The alkylating agent component, p-bis-(2-chloroethyl)aminophenoxy acetic acid, was shown to be less effective than the parent compound, while the modified steroid component, 3 beta-hydroxy-13 alpha-amino-13,17-seco-5 alpha-androstan-17-oic-13,17-lactam, showed no effect. There were no statistically significant differences among donors regarding the induction of SCEs and replication indices (RIs) for the compounds tested.
