Alteration of drug chemosensitivity caused by the adenovirus-mediated transfer of the wild-type p53 gene in human lung cancer cells

Abstract

The aim of the present study is to identify the optimal anticancer agents for use in combination with gene therapy using wild-type (wt) p53 gene transfer. We used adenoviral vectors expressing human wt p53 (AdCAp53) and investigated the effects of wt p53 gene transfer in combination with 12 anticancer agents on a human pulmonary squamous cell carcinoma cell line, NCI-H157, and a human pulmonary large cell carcinoma cell line, NCI-H1299. Solutions containing anticancer agents at various concentrations were added followed by the addition of recombinant adenovirus solutions; after a 5-day incubation period, the anticancer activity was then evaluated by a 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide assay. Each 50% inhibitory concentration was calculated based on the dose-response curves. The agents showing a high degree of effectiveness on NCI-H157 cells were cisplatin (CDDP), 5-fluorouracil (5-FU), bleomycin, and 7-ethyl-10-hydroxy-camptothecin (SN-38), an active metabolite of irinotecan (CPT-11); conversely, cyclophosphamide and paclitaxel showed a low degree of effectiveness. Based on these data, an isobologram was performed to investigate the interaction between AdCAp53 and some anticancer agents. A supra-additive effect was thus observed for 5-FU and SN-38 on NCI-H157 cells. An additive effect was also observed for CDDP, paclitaxel, bleomycin, and cyclophosphamide on NCI-H157 cells. CDDP, paclitaxel, 5-FU, and SN-38 had an additive effect on NCI-H1299 cells. No drug showed any subadditive or protective effects. These findings suggest that CPT-11 and 5-FU may thus be useful as possible anticancer agents for use in a combination therapy regimen using wt p53 gene transfer. CDDP and CPT-11 had a significant antitumoral effect on H157 cell xenografts of nude mice in vivo. These results indicate that CPT-11 as well as CDDP would be a candidate for the combination of chemotherapy and gene therapy for non-small cell lung cancer. Cancer Gene Therapy (2000) 7, 300 -307

A Systematic Review of Genes Involved in the Inverse Resistance Relationship Between Cisplatin and Paclitaxel Chemotherapy: Role of BRCA1

“…Sensitive No Change [42] Patients with BRCA mutation compared to healthy controls, mechanism not investigated H460 NSCLC ↑FHIT Adenovirus 0.57 1 [43] Fragile [45] Mechanism of Cisplatin sensitivity not investigated HeLa Ovarian ↑p53wt Adenovirus 0.68 0.93 [46] Increase in DNA fragmentation induced by cisplatin HFF Human Fibroblasts ↓RB E7 virus 0.53 0.93 [47] Mechanism of Cisplatin sensitivity not investigated MEF Mouse Fibroblasts ↓Xrcc2 Knockout mouse Sensitive No Change [48] Decrease in Homologous Recombination repair of DNA double strand breaks induced by cisplatin…”

p53 interferes with microtubule-stabilizing agent-induced apoptosis in prostate and colorectal cancer cells

“…Several studies have suggested that Taxol-induced apoptosis is independent of the p53 status (11)(12)(13)(14)(15)(16). In contrast, increased sensitivity to Taxol was observed in non-transformed cells in the absence of functional p53 (17).…”

Cellular effects of CPT‐11 on colon carcinoma cells: Dependence on p53 and hMLH1 status

“…13 In xenografts, a mutation in the p53 gene was associated with resistance to CPT-11 treatment of some colon carcinoma cell lines 14 and of a human lung cancer cell line. 15 The MMR status did not appear to have a decisive effect on the sensitivity to CPT-11 of colon carcinoma xenografts, 8,14 whereas in a retrospective clinical study of patients with metastatic colorectal cancer a correlation was found between microsatellite instability and tumor response to CPT-11. 16 Furthermore, some authors reported a correlation of the MMR defect in colorectal cancer cell lines with an increased sensitivity, 17 while others with resistance to topo I inhibitors.…”