Increased platinum-DNA damage tolerance is associated with cisplatin resistance and cross-resistance to various chemotherapeutic agents in unrelated human ovarian cancer cell lines.
We have examined a panel of 12 unrelated human ovarian cancer cell lines derived from patients who were either untreated or treated with platinum-based chemotherapy to determine whether a relationship is present between cisplatin sensitivity and: (a) cellular platinum accumulation; (b) glutathione levels; (c) platinum-DNA adduct formation; (d) platinum-DNA adduct removal; and (e) platinum-DNA damage tolerance. Multiple regression and correlation analysis revealed that of these resistance mechanisms, platinum-DNA damage tolerance correlates strongly with cisplatin sensitivity (r = 0.84, P = 0.001), whereas platinum accumulation (r = -0.11), cellular glutathione levels (r = 0.13), and platinum-DNA adduct removal (r = 0.44) correlate insignificantly. The correlation of platinum-DNA damage tolerance to cisplatin sensitivity (IC50s) is derived from the clustering of platinum-DNA adduct formation into three distinct groups spanning a 3-fold range, which is narrow relative to the corresponding 43-fold range in sensitivity. Adduct formation itself is not associated with cisplatin sensitivity (r = -0.38). Strong correlations were also observed between platinum-DNA damage tolerance and sensitivity to Adriamycin (r = 0.80, P = 0.002), paclitaxel (r = 0.87, P = 0.0002), etoposide (r = 0.78, P = 0.003), and mitomycin C (r = 0.73, P = 0.007). These results suggest that the failure of pathways that are involved in recognizing and processing platinum-DNA damage and other types of drug-induced damage that culminate in cell death may result in a broad resistance phenotype.
Johnson
S W
SW
Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
Laub
P B
PB
Beesley
J S
JS
Ozols
R F
RF
Hamilton
T C
TC
D000970:Antineoplastic Agents / Q000008:administration & dosage*; D002945:Cisplatin / Q000008:administration & dosage*; D004249:DNA Damage / Q000187:drug effects*; D004260:DNA Repair; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage; D004351:Drug Resistance; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D016685:Mitomycin / Q000008:administration & dosage; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D017239:Paclitaxel / Q000008:administration & dosage; D012044:Regression Analysis; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D016685:Mitomycin; D005047:Etoposide; D004317:Doxorubicin; D005978:Glutathione; D017239:Paclitaxel; D002945:Cisplatin