Cytotoxicity, cellular uptake and DNA binding of the novel trinuclear platinun complex BBR 3464 in sensitive and cisplatin resistant murine leukemia cells.
BBR 3464 is a novel trinuclear platinum anticancer agent designed on the hypothesis that new clinically useful platinum based anticancer agents should have novel structures unrelated to those of agents currently used in the clinic. BBR 3464 shows outstanding cytotoxicity both against sensitive (L1210) and cisplatin (CDDP) resistant (L1210/CDDP) murine leukemia cell lines. In fact, BBR 3464 is 30 times more cytotoxic than CDDP against the L1210 cell line and also shows a complete lack of cross-resistance in L1210/CDDP (resistance index 0.8). BBR 3464 and CDDP cellular uptake in L1210 and L1210/CDDP eells and binding to nuclear DNA were studied after incubation with 3.34 microM BBR 3464 and 66.7 microM CDDP, respectively, for up to 4 hours with 133.4 and 266.8 microM of CDDP and 6.68, 13.36 microM of BBR 3464 for 2 hours to determine concentration-cellular uptake and concentration-DNA binding relationships. CDDP and BBR 3464 cellular uptake and their extent of binding to DNA increased as function of time and in a concentration dependent manner in both cell lines. CDDP uptake and binding to DNA were higher in L1210 eells than in L1210/CDDP cells whereas BBR 3464 uptake and binding to DNA were similar in both cell lines. In L1210/CDDP murine leukemia cells BBR 3464 seems to overcome the CDDP cross-resistance related to impaired accumulation and reduction of binding to DNA.
Di Blasi
P
P
Boehringer Mannheim Italia, Research Center, Monza, MI, Italy.
Bernareggi
A
A
Beggiolin
G
G
Piazzoni
L
L
Menta
E
E
Formento
M L
ML
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D002945:Cisplatin / Q000493:pharmacokinetics / Q000494:pharmacology*; D004273:DNA, Neoplasm / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D007700:Kinetics; D007939:Leukemia L1210 / Q000188:drug therapy* / Q000378:metabolism*; D051379:Mice; D009944:Organoplatinum Compounds / Q000493:pharmacokinetics / Q000494:pharmacology*; D012680:Sensitivity and Specificity
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D009944:Organoplatinum Compounds; C114062:BBR 3464; D002945:Cisplatin