Cellular pharmacology of liposomal cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexaneplatinum(II) in A2780/S and A2780/PDD cells.
We studied the cytotoxicity, cellular accumulation, and DNA interactions induced by liposome-entrapped NDDP (L-NDDP) and cisplatin in A2780 human ovarian carcinoma cells sensitive (A2780/S) and resistant (A2780/PDD) to cisplatin. L-NDDP was 2-fold more cytotoxic than cisplatin against A2780/S cells with 5-h or 24-h drug exposure. Both cell lines were equally sensitive to L-NDDP, while A2780/PDD cells were 4-fold resistant to cisplatin (resistance indexes, 1.30-1.85 and 4.02-4.50, respectively). Using a drug exposure time of 24 h, L-NDDP cytotoxicity was independent of the liposome composition used, whereas with shorter drug exposure (5 h), the cytotoxicity of L-NDDP was directly related to the relative content of DMPG in the liposome carrier. However, changes in liposome composition or drug exposure time did not alter the resistance index of L-NDDP in this cell system. The cellular accumulation of L-NDDP was similar in both cell lines and 2- to 5-fold higher than that of cisplatin in A2780/S cells, whereas the cellular accumulation of cisplatin was reduced by 2- to 3-fold in A2780/PDD cells. The presence of DMPG in the lipid bilayer enhanced by 2-fold the cellular accumulation of L-NDDP, in good correlation with the direct relation between cytotoxic potency of L-NDDP and the presence of DMPG in the liposome carrier. Pt/DNA levels were determined at different time points after drug exposure for 1 h. Peak Pt/DNA levels were observed at 6 h for cisplatin and at 9 h for L-NDDP. Peak Pt/DNA levels and Pt/DNA over time of L-NDDP were about 1.5- and 3-fold higher than those of cisplatin in A2780/S and A2780/PDD cells, respectively, when equimolar concentrations of both drugs were used. Cisplatin induced significant DNA interstrand and DNA-protein cross-links in A2780/S cells, and a good correlation was observed between cytotoxicity against both cell lines and both types of lesions. In contrast, equimolar concentrations of L-NDDP induced only minimal DNA interstrand cross-links in either cell line.(ABSTRACT TRUNCATED AT 400 WORDS)
Han
I
I
Department of Thoracic/Head and Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston 77030.
Ling
Y H
YH
al-Baker
S
S
Khokhar
A R
AR
Perez-Soler
R
R
D000970:Antineoplastic Agents / Q000378:metabolism / Q000633:toxicity; D001692:Biological Transport; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000378:metabolism* / Q000633:toxicity*; D004273:DNA, Neoplasm / Q000032:analysis; D004134:Dimyristoylphosphatidylcholine; D004337:Drug Carriers; D004351:Drug Resistance; D005260:Female; D006801:Humans; D007700:Kinetics; D008081:Liposomes; D009944:Organoplatinum Compounds / Q000378:metabolism* / Q000633:toxicity*; D010051:Ovarian Neoplasms; D010715:Phosphatidylglycerols; D010984:Platinum / Q000032:analysis; D013054:Spectrophotometry, Atomic; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D004337:Drug Carriers; D008081:Liposomes; D009944:Organoplatinum Compounds; D010715:Phosphatidylglycerols; C054367:bis-neodecanoato-1,2-diaminocyclohexaneplatinum(II); D010984:Platinum; C002773:dimyristoylphosphatidylglycerol; D002945:Cisplatin; D004134:Dimyristoylphosphatidylcholine