Cytogenetic and antineoplastic effects of modified steroidal alkylators.
BACKGROUND
The aim of this study was to design new potentially antineoplastic agents by combining nitrogen mustard with steroidal skeleton, in an effort to improve specificity and simultaneously to reduce systemic toxicity. The steroidal part is aimed to act as a biological platform enabling the alkylating moiety to approach its site of action by altering its physicochemical properties.


METHODS
The compounds tested have, as alkylating agents, either p-N,N-bis(2-chloroethyl)aminophenyl-butyrate or p-N,N-bis(2-chloroethyl)aminophenyl-acetate esterified with a modified steroidal nucleus. The four newly synthesized compounds were compared on a molar basis, regarding their ability to induce sister chromatid exchanges and modify proliferation rate indices in cultured human lymphocytes. Life span of BDF1 mice inoculated with L1210 leukemia was also estimated (antileukemic activity).


RESULTS
A compound having p-N,N-bis(2-chloroethyl)aminophenyl-acetate as the alkylator and two ketone groups in the steroidal part demonstrated the highest statistically significant enhancement of sister chromatid exchanges and suppression of proliferation rate indices, and also caused significant antineoplastic activity. The other compounds proved less active.


CONCLUSIONS
These results suggest that cytogenetic and antileukemic activity of alkylating steroidal esters depends on the configuration of the whole molecule and the appropriate combination of the alkylator with the steroidal molecule.
Karapidaki
Irini
I
Laboratory of Biology and Genetics, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece.
Papageorgiou
Athanasios
A
Geromichalos
George
G
Fousteris
Manolis
M
Papaconstadinou
Ioanna
I
Pairas
George
G
Koutsourea
Anna
A
Mourelatos
Denis
D
Nikolaropoulos
Sotiris
S
Lialiaris
Theodoros
T
D000731:Androstanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D066298:In Vitro Techniques; D007939:Leukemia L1210 / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects; D051379:Mice; D015394:Molecular Structure; D012854:Sister Chromatid Exchange / Q000187:drug effects
D000731:Androstanes; D018906:Antineoplastic Agents, Alkylating