Tamoxifen delays the development of resistance to cisplatin in human melanoma and ovarian cancer cell lines

Abstract

Summary The development of resistance to cisplatin (DDP) occurs rapidly both in vitro and in vivo, and constitutes a major obstacle to effective therapy. We have previously demonstrated that there is a highly synergistic interaction between tamoxifen (TAM) and DDP against cell lines representative of three different human cancers: melanoma, ovarian carcinoma and small-cell lung cancer. The purpose of these studies was to determine if TAM interferes with the development of resistance to DDP. T-289 Our previous clinical studies have demonstrated that tamoxifen (TAM) is an important component of a four-drug combination of dacarbazine, carmustine, DDP and TAM in the treatment of patients with metastatic melanoma (McClay et al., 1987). Omission of TAM from the regimen resulted in a decrease in the overall response rate from 51% to 10% (McClay et al., 1989). Reincorporation of TAM into the regimen resulted in a return of the response rate to more than 50% (McClay et al., 1992a). In a recent clinical study we demonstrated that, in patients with malignant melanoma documented to be resistant to single-agent DDP, the addition of TAM to the DDP programme on the next cycle resulted in a response rate of 30% (McClay et al., 1993a al., 1992b, 1993b). However, the DDP/TAM synergy was dependent on the sensitivity of the cell to TAM. DDP and TAM were still synergistic with respect to cytotoxicity in a DDP-resistant variant of the T-289 melanoma cell line, however they were not synergistic in killing a variant of the same cell line selected for resistance to TAM (McClay et al., 1993b). Synergy was also absent in another melanoma cell line that was 4-fold resistant to TAM (McClay et al., 1992b). (McClay et al., 1993c).Although the mechanism of synergy between TAM and DDP is not known at present, we hypothesised that if TAM can synergise with DDP to overcome DDP resistance then TAM may also be able to delay the development of DDP resistance by a similar mechanism. We report here that TAM can delay the development of DDP resistance in both T-289 and 2008 cells when given concurrently with DDP in cell culture.

A phase II study of two cycles of high-dose chemotherapy with autologous stem cell support in patients with metastatic breast cancer who meet eligibility criteria for a single cycle

“…The use of tamoxifen in this context was based upon previous reported studies from our institution describing synergism between high doses of tamoxifen and platinum chemotherapy. [17][18][19] Prophylactic heparin (5000 units s.c. three times daily day −5 to 0 ) was used to minimize the risk of thromboembolic complications. PBSC +/− BM were re-infused on day 0 as for HDC cycle I.…”

Mitogen-activated protein kinase inhibits 1,25-dihydroxyvitamin D3–dependent signal transduction by phosphorylating human retinoid X receptor α

“…Resistance to anti-tumor agents is often a limiting factor in cancer therapy (1). Activation of ras, the most common oncogene implicated in human cancer, has been detected in a wide variety of tumors, including carcinomas of the pancreas and squamous tumors of the colon, lung, skin, and breast (2).…”

“…The biologically active form of vitamin D 3 , 1,25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ], directly modulates the transcription of several target genes by binding to the vitamin D 3 receptor (VDR), a member of the nuclear receptor family of transcriptional regulators. The ligand-bound VDR functions as a heterodimer by interacting with members of the retinoid X receptor (RXR) family of nuclear receptors (5).…”

A Phase III Trial Evaluating the Combination of Cisplatin, Etoposide, and Radiation Therapy With or Without Tamoxifen in Patients With Limited-Stage Small Cell Lung Cancer

“…Despite encouraging in vitro data demonstrating that TAM can enhance the effectiveness of several chemotherapeutic agents, there has only been 1 randomized clinical study to support its effectiveness in vivo. 7,9,17 Cocconi et al demonstrated a modest survival advantage for patients with metastatic melanoma treated with the combination of TAM/ DTIC over those treated with DTIC as a single agent. 18 Unfortunately, the current study joins a growing list of studies that have failed to demonstrate a survival advantage when TAM is added to cisplatin-containing regimens.…”

“…The median OS for patients treated without tamoxifen is 20.6 months (95% CI, 17.0 -24.7) and for patients treated with tamoxifen it is 18.4 months (95% CI, 16.4 -22.0). At 3 years, the FFS for patients without tamoxifen is 23% (95% CI, [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31], and for patients treated with tamoxifen it is approximately 22% (95% CI, 16 -29). The OS for patients without tamoxifen at 3 years is 30% (95% CI, [23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38], and for patients treated with tamoxifen it is 25% (95% CI, 19 -33).…”