Dioxopiperazine derivative potentiates antitumor effect of methylglyoxal bis(cyclopentylamidinohydrazone) on human and mouse leukemia cells.
Antiproliferative effects of 1,1'-ethylenedi-4-isobutoxy-carbonyloxymethyl-3,5-d iox opiperazine (MST-16), an inhibitor of topoisomerase II, in combination with methylglyoxal bis (cyclopentylamidinohydrazone) (MGBCP), an inhibitor for polyamine biosynthetic enzymes, were investigated using cultured human lymphoid cells and leukemic mice. The combined treatment of human Molt 4B lymphoid cells with MST-16 and MGBCP resulted in greater suppressions of cellular polyamine and protein biosyntheses and decrease of cell number than in the cells treated with either drug alone. Inhibition of macromolecule biosyntheses by MGBCP was additively potentiated by simultaneous treatment with MST-16. In vivo experiments, the combination of MST-16 and MGBCP markedly prolonged the survival time of mice bearing P388 or L1210 leukemia. These results suggest that good antitumor activity of combined treatment with MST-16 and MGBCP resulted from the diminution of DNA condensation and cellular proliferation caused by inhibition of topoisomerase II with MST-16 and by polyamine depletion with MGBCP.
College of Medical Sciences, Mie University, Japan.
H
H
Hibasami
T
T
Tsukada
S
S
Shirakawa
T
T
Narita
M
M
Inagaki
K
K
Nakashima
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects; D003433:Crosses, Genetic; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007700:Kinetics; D007939:Leukemia L1210; D007941:Leukemia P388; D007945:Leukemia, Lymphoid; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008935:Mitoguazone / Q000031:analogs & derivatives* / Q000633:toxicity; D010879:Piperazines / Q000633:toxicity*; D011073:Polyamines / Q000378:metabolism*; D011700:Putrescine / Q000378:metabolism; D013095:Spermidine / Q000378:metabolism; D013096:Spermine / Q000378:metabolism; D013997:Time Factors; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D010879:Piperazines; D011073:Polyamines; C059234:methylglyoxal bis(cyclopentylamidinohydrazone); D013096:Spermine; D008935:Mitoguazone; C057773:sobuzoxane; D013095:Spermidine; D011700:Putrescine