Comparison of cytotoxicity and cellular accumulation of polynuclear platinum complexes in L1210 murine leukemia cell lines.
The antitumor activity of the trinuclear Phase I clinical agent, BBR3464, is matched by that of polyamine-linked dinuclear complexes. The cytotoxicity and cellular accumulation of three polynuclear platinum complexes: [¿trans-PtCl(NH3)2¿2 mu-¿trans-Pt(NH3)2(H2N(CH2)6-NH2)2¿]4+ (BBR3464), [¿trans-PtCl(NH3)2¿2(H2N(CH2)3NH2(CH2)4NH2)]3+ (BBR3571), and [¿trans-PtCl(NH3)2¿2(H2N(CH2)6-NH2)]2+ (BBR3005), were studied in a series of murine L1210 cell lines and compared with cisplatin. Besides murine L1210 cell lines sensitive (/0) and resistant (/DDP) to cisplatin, the efficacy of the compounds in a cell line rendered resistant to BBR3464 (/3464) was examined. Finally, to examine possible uptake pathways of these novel charged complexes, cytotoxicity in a cell line resistant to the polyamine synthesis inhibitor, methylglyoxal-bis(guanylhydrazone) (/MGBG), was studied. Cytotoxicity profiles of BBR3571 most closely matched that of BBR3464. Both agents showed significantly reduced cytotoxicity in L1210/ BBR3464. The cytotoxicity of neither agent was affected by the polyamine uptake-deficient cell line and indeed both complexes showed significantly enhanced cytotoxicity in L1210/MGBG relative to wild-type L1210/0. The cellular uptake of both BBR3464 and BBR3571 was enhanced in L1210/DDP. These studies suggest that the chemical feature of a diamine linker containing an internal charge contributes significantly to the anticancer profiles of both the trinuclear platinum complex, BBR3464, which incorporates a charged platinum into a diamine linker, and the dinuclear platinum complex, BBR3571, which incorporates only a naturally occurring polyamine as diamine linker.
Roberts
J D
JD
Massey Cancer Center, Virginia Commonwealth University, Richmond 23284-2006, USA.
Peroutka
J
J
Beggiolin
G
G
Manzotti
C
C
Piazzoni
L
L
Farrell
N
N
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D007939:Leukemia L1210 / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008935:Mitoguazone / Q000494:pharmacology; D009944:Organoplatinum Compounds / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; C403611:BBR 3571; D004791:Enzyme Inhibitors; D009944:Organoplatinum Compounds; C059267:dichlorotetraamine(1,6-hexamethylenediamine)diplatinum(II); C114062:BBR 3464; D008935:Mitoguazone; D002945:Cisplatin