title: Preclinical studies on NSC290205 aza-steroid alkylator activity in combination with adriamycin against lymphoid leukaemia.
abstract: Summary NSC290205 (A) is an hybrid synthetic antineoplastic ester that is a combination of a d-lactam derivative of androsterone and an alkylating derivative of N,N-bis(2-chloroethyl)aniline. We tested NSC290205 for synergistic antileukaemic activity with adriamycin (ADR), (i) in vitro against the human lymphoid leukaemia cell lines: CCRF-CEM, MOLT-4, and RPMI-8226, (ii) in vivo against P388 lymphocytic and L1210 lymphoid murine leukaemias (at incipient and advanced phase). Our results indicated significant cytostatic and cytotoxic synergy of NSC290205 and ADR in vitro. We further examined these results in vivo by replacing cyclophosphamide in the standard CHOP (cyclophosphamide, hydroxydaunomycin, Oncovin, prednisone) regimen with NSC290205 (AHOP) and comparing the efficiency of these two regimens in vivo. Although treatment of P388 and L1210 with cyclophosphamide or NSC290205 alone yielded equivalent results, AHOP produced a clear benefit for survival compared with CHOP against advanced leukaemias, confirming the in vitro observations [higher percentage increase in median lifespan of treated animals over the untreated (control): 188% and 239% in L1210, 308% and 353% in P388, P < 0.01, for CHOP and AHOP respectively]. AHOP also proved to be more genotoxic and cytostatic than CHOP, inducing higher sister chromatid exchange levels and cell division delays on P388 cells in vivo. NSC290205 showed superior antineoplastic potential against lymphoid leukaemia and significant synergy with ADR, producing an excellent therapeutic outcome.
authors.affiliation: Laboratory of Medicinal Chemistry, Department of Pharmacy, University of Patras, Patras, Greece. dtrafalis@yahoo.com
authors.forename: Dimitrios T P
authors.initials: DT
authors.lastname: Trafalis
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Tsavdaridis
authors.forename: Charalambos
authors.initials: C
authors.lastname: Camoutsis
authors.forename: Venetia
authors.initials: V
authors.lastname: Karayiani
authors.forename: Dionysios
authors.initials: D
authors.lastname: Mourelatos
authors.forename: Panayotis
authors.initials: P
authors.lastname: Dalezis
authors.forename: Athanasios
authors.initials: A
authors.lastname: Athanassiou
authors.forename: Gerassimos A
authors.initials: GA
authors.lastname: Pangalis
authors.forename: Athanasios
authors.initials: A
authors.lastname: Papageorgiou
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D001378:Azasteroids / Q000008:administration & dosage; D016923:Cell Death / Q000187:drug effects; D003520:Cyclophosphamide / Q000627:therapeutic use; D004317:Doxorubicin / Q000008:administration & dosage / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D006801:Humans; D007942:Leukemia, Experimental / Q000188:drug therapy* / Q000473:pathology; D007945:Leukemia, Lymphoid / Q000473:pathology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009368:Neoplasm Transplantation; D009588:Nitrogen Mustard Compounds / Q000008:administration & dosage; D011241:Prednisone / Q000627:therapeutic use; D016019:Survival Analysis; D014407:Tumor Cells, Cultured; D014750:Vincristine / Q000627:therapeutic use
chemical_list: D001378:Azasteroids; D009588:Nitrogen Mustard Compounds; C017888:NSC 290205; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone