| Title: |
Mechanisms associated with the expression of cisplatin resistance in a human ovarian tumor cell line following exposure to fractionated X-irradiation in vitro |
| Authors: |
Dempke, Wolfram C.M.; Shellard, Sharon A.; Hosking, Louise K.; Fichtinger-Schepman, Anne Marie J.; Hill, Bridget T. |
| Publisher Information: |
Oxford University Press |
| Publication Year: |
1992 |
| Collection: |
HighWire Press (Stanford University) |
| Subject Terms: |
COMMENTARY |
| Description: |
Interactions between cisplatin (CDDP) and irradiation are of potential significance for the combined modality treatment of cancer. Previous data have indicated that following in vitro exposure to X-irradiation certain tumour cells expressed resistance to CDDP. To identify parameters associated with this CDDP resistance, the human ovarian carcinoma cell line SK-OV-3/P was pre-exposed to fractionated X-irradiation (total dose: 50 Gy) in vitro . The resultant subline (SK-OV-3/DXR-10) proved 2-fold resistant to CDDP, but not to acute X-irradiation. Consistent with unaltered dihydrofolate reductase and thymidylate synthase activities, SK-OV-3/DXR-10 cells were neither cross-resistant to methotrexate nor to 5-fluorouracil. Verapamil (6.6 µM) significantly (P < 0.05) enhanced CDDP-induced cytotoxkity in the resistant DXR-10 subline, but not in the parental cells. Total glutathione levels were significantly (P < 0.01) lower in the resistant subline and BSO pretreatment failed to influence cytotoxicity, whilst related enzyme activities were not consistently modified in the SK-OV-3/DXR-10 cells. Resistance in these cells was associated with significantly decreased cisplatin uptake (P < 0.002). Immediately following drug exposure the total platlnation level of the DNA, quantitated immunochemically, was higher (P < 0.05) in the resistant subline indicative of increased tolerance to DNA damage. After an 18 h post-treatment incubation the parental cell line appeared proficient in the removal of the intrastrand adduct Pt-AG, but deficient in removing the major adduct Pt-GG and the difunctional Pt-(GMP) 2 lesion, whilst the DXR-10 resistant subline appeared proficient in removal of all four Pt-DNA adducts. DNA polymerases α and β activities, however, were comparable in both cell lines. These data implicate both enhanced repair and increased tolerance of DNA damage as mechanisms of resistance to CDDP resulting from in vitro exposure of a human ovarian carcinoma cell line to fractionated X-irradiation. |
| Document Type: |
text |
| File Description: |
text/html |
| Language: |
English |
| Relation: |
http://carcin.oxfordjournals.org/cgi/content/short/13/7/1209; http://dx.doi.org/10.1093/carcin/13.7.1209 |
| DOI: |
10.1093/carcin/13.7.1209 |
| Availability: |
http://carcin.oxfordjournals.org/cgi/content/short/13/7/1209; https://doi.org/10.1093/carcin/13.7.1209 |
| Rights: |
Copyright (C) 1992, Oxford University Press |
| Accession Number: |
edsbas.31C956B2 |
| Database: |
BASE |