Single-agent gemcitabine and gemcitabine/irinotecan combination (irimogem) in non-small cell lung cancer.

Gemcitabine is a fluoridated pyrimidine related to cytosine arabinoside that has significant activity in solid tumor models. Irinotecan is a camptothecin analog with an active metabolite, SN-38, which inhibits topoisomerase I activity by stabilizing the topoisomerase I-DNA cleavable complex. Gemcitabine studies in non-small cell lung cancer conducted in the United States, as well as an international collaboration and clinical trials from Europe and Japan, found overall response rates of 20% to 26%, a median duration of response between 5 to 9 months, and a median duration of survival ranging from 7 to 12.3 months. Gemcitabine also has been shown to be more effective than best supportive care in non-small cell lung cancer. In a phase I trial of irinotecan (50, 75, 100, and 115 mg/m2) in combination with 1,000 mg/m2 gemcitabine, three patients had documented partial responses: one with pancreas cancer at irinotecan 100 mg/m2, one with pancreas cancer, and one with metastatic carcinoma of unknown primary at irinotecan 115 mg/m2. Three of five non-small cell lung cancer patients had stable disease for four or more cycles at irinotecan doses of 50, 75, and 100 mg/m2; no non-small cell lung cancer patients were treated at irinotecan 115 mg/m2. We recommend that a combination of gemcitabine 1,000 mg/m2 and irinotecan 100 mg/m2 given on days 1 and 8 every 3 weeks be used as the starting dose in future phase II studies. Furthermore, based on the absence of severe nonhematologic toxicity or grade IV hematologic toxicity in the majority of patients treated at the highest dose, escalation of irinotecan to 115 mg/m2 may be considered for subsequent cycles in patients who do not experience > or =grade I hematologic or non-hematologic toxicity during the first cycle of gemcitabine/irinotecan combination chemotherapy.

Synergistic interaction between topotecan and microtubule-interfering agents.

PURPOSE: Topotecan is a topoisomerase I inhibitor with demonstrated anticancer activity in preclinical and clinical studies. The purpose of the present study was to evaluate drug-drug interactions in therapeutic regimens that would combine topotecan with microtubule-interfering agents, such as Taxol and vinblastine. METHODS: The cytotoxic activities of various drug combinations and schedules of administration were measured in a colon cancer cell line using the MTT assay. Western blot and flow cytometry were performed to determine the effects of Taxol and vinblastine on topoisomerase I and Bcl-xL protein levels and cell cycle distribution. RESULTS: Brief incubation of colon cancer cells with low concentrations of either Taxol or vinblastine increased the efficacy of a subsequent treatment with topotecan. Preincubation of cells with vinblastine or Taxol reduced by 10- to 40-fold the concentration of topotecan necessary to induce a 50% decrease in cell survival. The effects were maximal when the cells were treated for 5 h with microtubule-interfering agents and then incubated for 19 h in drug-free medium before the addition of topotecan. Under these conditions, both Taxol and vinblastine caused an increase in topoisomerase I protein levels, fraction of S phase cells, and extent of Bcl-xL phosphorylation immediately prior to the addition of topotecan. All these factors may contribute to the increased efficacy of topotecan observed with sequential therapy. CONCLUSION: Combinations of topotecan and microtubule-interfering agents result in synergistic anticancer activity when the drugs are administered sequentially. The promising preclinical data presented here encourage clinical testing of these drug combinations using a sequential schedule of administration.

Synergistic effect of gemcitabine and irinotecan (CPT-11) on breast and small cell lung cancer cell lines.

Gemcitabine (2'-2'-difluorodeoxycytidine, dFdC), an analog of deoxycytidine, is an antineoplastic agent with clinical activity against several types of cancer. Irinotecan (CPT-11), a topoisomerase I inhibitor, is a drug with a broad spectrum of anticancer activity. Since these drugs have different mechanisms of cytotoxicity and dose-limiting toxicity profiles, preclinical combination studies were performed on the MCF-7 breast cancer and the SCOG small cell lung cancer (SCLC) cell lines. Both gemcitabine and CPT-11 as single agents were effective growth inhibitors in these cell lines. Isobologram analysis revealed for the first time that the combination of these drugs exerted synergy over a wide range of concentrations in MCF-7 and SCOG cells. Moreover, combination index (CI) analysis revealed that at low concentrations, combinations of gemcitabine and CPT-11 show a synergistic growth inhibitory effect on MCF-7 cells. However, in SCOG cells CI analysis showed synergy at concentrations of gemcitabine and CPT-11 greater than 1 microM but antagonism at combination concentrations less than 1 microM. These preclinical cytotoxicity data provide an experimental basis for conducting clinical trials using combinations of gemcitabine and CPT-11, especially in patients with breast and lung cancers.

Co-ordinated over-expression of the MRP and gamma-glutamylcysteine synthetase genes, but not MDR1, correlates with doxorubicin resistance in human malignant mesothelioma cell lines.

While human malignant mesothelioma is extremely resistant to chemotherapy, its intrinsic resistance mechanisms remain largely unknown. In this study, we used normal human mesothelial cells and 5 human mesothelioma cell lines not previously exposed to chemotherapeutic agents to demonstrate that the mRNA for the multidrug resistance-associated protein (MRP) and gamma-glutamylcysteine synthetase (gamma-GCSh) heavy subunit genes, but not the P-glycoprotein (MDR1) gene, are co-ordinately over-expressed in mesothelioma cell lines. Expression of MRP as detected with an anti-MRP antibody correlated with decreased doxorubicin accumulation and resistance of mesothelioma cells to this drug. Our results strongly suggest roles for MRP and gamma-GCSh in chemoresistance in mesotheliomas.