Synergistic cytogenetic and antineoplastic effects by the combined action of esteric steroidal derivatives of nitrogen mustards.
We studied the effect of five newly synthesized steroidal derivatives of nitrogen mustards. These derivatives have as alkylators either P-N, N-bis(2-chloroethyl)aminophenyl-butyrate (CHL) or P-N, N-bis(2-chloroethyl)aminophenyl-acetate (PHE) groups esterified with different modified steroidal nuclei. We examined them alone or in combination, on sister chromatid exchange rates and on human lymphocyte proliferation kinetics. The antitumor activity of these compounds, alone or in combination, was also tested on Leukemia P388-bearing mice. A pronounced cytogenetic and antineoplastic action was demonstrated by the compounds that contain either PHE or CHL as alkylators and are esterified with a steroidal nucleus having added a cholestene group in the 17 position of the D-ring. The exocyclical insertion of an -NHCO- group in the D-ring of the steroidal nucleus esterified with PHE (amide ester of PHE) yielded a compound demonstrating a distinct cytogenetic and antineoplastic effect. In contrast, the ketone group in the D-ring being inserted endocyclically in the steroidal nucleus (androstene) esterified with either CHL or with PHE gave negative cytogenetic and antineoplastic effects. However, the combined action of cholestene esterified with either CHL or with PHE in combination with either the androstene ester of PHE or with the androstene ester of CHL, respectively, gave synergistic cytogenetic and antineoplastic effects. Also the amide ester of PHE in combination with the androstene ester of CHL gave distinct cytogenetic and antineoplastic effects in a synergistic manner.
Laboratory of Genetics, Medical School, Dimokrition University of Thrace, Alexandroupolis, Greece.
Constantinos
C
Mourelatos
Sotiris
S
Nikolaropoulos
Manolis
M
Fousteris
Georgios
G
Pairas
Maria
M
Argyraki
Dimitra
D
Kareli
Evaggelia
E
Dafa
Dionisios
D
Mourelatos
Theodore
T
Lialiaris
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D004952:Esters / Q000737:chemistry; D006801:Humans; D007941:Leukemia P388 / Q000188:drug therapy*; D008213:Lymphocyte Activation / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009588:Nitrogen Mustard Compounds / Q000737:chemistry* / Q000494:pharmacology; D012854:Sister Chromatid Exchange / Q000187:drug effects*; D013256:Steroids / Q000737:chemistry; D016896:Treatment Outcome
D018906:Antineoplastic Agents, Alkylating; D004952:Esters; D009588:Nitrogen Mustard Compounds; D013256:Steroids