Expression of ERCC1 protein in biopsy specimen predicts survival in advanced ovarian cancer patients treated with platinum-based chemotherapy.

PURPOSE: The purpose of this study was to investigate whether the expression of excision repair cross complementing 1 (ERCC1) protein I in tumor tissue was associated with resistance to standard carboplatin and paclitaxel (PC) combination chemotherapy in patients newly diagnosed with advanced epithelial ovarian carcinoma (EOC). METHODS: Fresh frozen tumor tissue was obtained from EOC patients. The protein expression levels of ERCC1 in tumor tissue were determined by Western blot analysis in 55 samples with advanced and metastatic EOC with different histologic subtypes; then these patients were treated with PC. RESULTS: The results showed that the clinical objective responses were significantly different in different categories of ERCC1 protein expression levels in patients with EOC. Time to progression (TTP) and overall survival (OS) in EOC patients previously treated with platinum-based chemotherapy were significantly longer in those with low expression compared with patients showing high expression of ERCC1 protein. CONCLUSION: Our results revealed that ERCC1 protein expression could potentially be used to customize chemotherapy by defining subsets of patients who would benefit the least from platinum-based chemotherapy.

Comparison between CoFactor and Leucovorin activity applied in combination with 5-fluorouracil against two human colon cancer cell lines.

PURPOSE: The reduced folate leucovorin (LV) has been used for over 30 years as an enhancer of 5-fluorouracil (5-FU) antitumor activity. CoFactor (CoF) is a calcium salt of LV's active metabolite. Thus, administration of CoF can prevent decrease of intratumoral folate, which was recognized as the main reason for resistance of tumors to 5-FU treatment. The aim of this study was to investigate the cytotoxic activity and type of interactions for 5-FU and CoF applied in combination, in comparison to combination of 5-FU and LV, against human colon cancer cell lines LS- 174 and HT-29. METHODS: The single agent activity was estimated in concentration range from 0.1 to 300 microM for 5-FU, CoF, and LV. In combined treatment each concentration of 5-FU (0.1, 1 and 10 microM) was matched with each concentration of CoF or LV (1, 10 and 100 microM). In both experiments the sulforodamine B cytotoxic test was used to assess drugs' activity after 72 h of incubation with cells. The type of interactions in combinations was calculated with the isobole method. RESULTS: 5-FU showed similar activity against LS-174 and HT-29 cell lines (IC50=30.8 and 21.6 microM, respectively). While LV affected both cell lines in a slightly proliferative manner, CoF showed cytotoxic effect on both cell lines, being more active against HT-29 cell (IC50=25.7 microM) and less active on LS-174 cells (IC50=72.6 microM). Addition of LV did not change the cytotoxicity of 5-FU, especially against LS-174 cells, and synergism was found only in HT-29 cells when LV was applied in high concentrations (10 and 100 microM). However, the combination of 5-FU with CoF revealed synergistic and additive interactions in LS-174 and HT-29 cells, respectively. CONCLUSION: These results should be taken into consideration when planning or analyzing the results of clinical trials using combination of CoF and 5-FU.

Mammalian target of rapamycin is a promising target for novel therapeutic strategy against cancer.

Mammalian target of rapamycin (mTOR) is a serine-threonine kinase member of the cellular phosphatidylinositol 3-kinase (P13K) pathway. The P13K/Akt signaling pathway plays a critical role in regulating basic cellular functions such as control of transcription and translation. mTOR is a downstream mediator of P13K/Akt and, as a result of its position, it has a central role in controlling cellular growth and division. Previous reports demonstrated that rapamycin, which inhibits mTOR activity, sensitizes certain resistant cancer cells to chemotherapeutic agents. These facts have made mTOR to be viewed as an important target for anti-cancer therapeutics development. Evidence suggests that the rapamycin derivatives CCI-779 and RAD001 could induce G1-S cell cycle delay and eventually apoptosis, depending on inner cellular characteristics of tumor cells. At present, CCI-779 and RAD001 are being evaluated in cancer clinical trials. From recent studies, these drugs appear to have a safe toxicity profile with skin rashes and mucositis being prominent and dose-limiting. In this review we discuss about the principal mechanisms of mTOR action and the current place of mTOR inhibitors as novel therapeutic agents against cancer.