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We chose to treat malignant pleural mesothelioma with a combination of docetaxel and irinotecan (CPT-11), because there have been preliminary reports that CPT-11 is active against mesothelioma, and docetaxel and CPT-11 were the most active agents in our in vitro experiments in human mesothelioma cell lines. Fifteen previously untreated patients with pleural mesothelioma (IMIG Stage III-IV) were given docetaxel 60 mg/m2 followed by CPT-11 190 mg/m2 on day 1, repeated every 3 weeks. All the patients were evaluable for toxicity and 13 patients were evaluated for response. No objective responses (complete or partial) were achieved, but there were two minor responses (overall response rate 15%) each of a duration of 4 months. Three patients had stable disease (23%); median time to progression was 7 months. Median survival in all the patients was 8.5 months from the first chemotherapy cycle and 11 months from diagnosis. Toxicity was severe with seven of 15 patients suffering neutropenic fever and six of 15 patients grade 3-4 diarrhea. The trial was discontinued because of toxicity and lack of activity. We do not recommend the combination of docetaxel and CPT-11 using the schedule presented here for further investigation in malignant mesothelioma. However, CPT-11 and docetaxel, individually, still warrant further study in this disease, especially in combination with cisplatin.

In this study, we used four human mesothelioma cell lines (M14K, M24K, M25K and M38K), one transformed human mesothelial cell line (MeT-5A) and one primary mesothelial culture (UPL) to test for in vitro sensitivity to docetaxel, paclitaxel, SN-38 [an active metabolite of irinotecan (CPT-11)] and gemcitabine, as single agents. Subconfluent cell cultures were treated with 2x10(-9), 5x10(-9), 10(-8), 2x10(-8) and 5x10(-8) M concentrations of each drug for 48 h. The sensitivity was measured in terms of cell viability using the Trypan blue exclusion method. All four drugs were potent inhibitors of mesothelioma cell growth, but cell lines from different patients diverged in their sensitivity to the individual agents. In most cases docetaxel, paclitaxel and SN-38 were more potent killers of mesothelioma cells than gemcitabine. The induction of DNA damage was investigated using the Comet assay; cells from two cell lines (M14K and M25K) were treated with subtoxic 10(-8) M concentrations of each drug for 4, 24 and 48 h. Each of the agents caused a slight increase in DNA single-strand breaks at a concentration of 10(-8) M.

Mesothelioma is a malignant tumor of the serous surfaces in the thorax and abdomen, which has proved exceptionally resistant to treatment. A recent phase II trial of a high-dose methotrexate regime on 63 Norwegian patients has, however, achieved a response rate of 37%. Some responses have also been achieved using interferon (IFN)-gamma administered intrapleurally or recombinant (r) IFN-alpha administered subcutaneously. Our earlier in vitro sensitivity studies of mesothelioma cell lines showed that IFN augments the response to chemotherapeutic agents in mesothelioma. The aim of this study was to assess the response of four mesothelioma cell lines, derived from diffuse asbestos-related pleural malignant mesothelioma, to methotrexate alone and in combination with recombinant IFN-alpha and IFN-gamma. Anti-proliferative effects were assayed by vital dye exclusion. A combination of IFN-alpha and IFN-gamma consistently augmented the response of the cell lines to methotrexate, by as much as 75% for one cell line, although the response to the individual IFNs was variable. We were also able to compare the effects of natural IFN-beta with those of IFN-alpha and IFN-gamma. The IFN-beta sensitivity profile for each of the four cell lines was similar to that of IFN-alpha. In two cell lines, the combination of IFN-beta and IFN-gamma produced a similar effect to the IFN-alpha and IFN-gamma combination.

Non-small cell lung cancers (NSCLC) are often resistant to chemotherapy. Cisplatin has shown the most activity against all the histological subtypes and is now used in most combined treatment programmes. Interferon (IFN)-alpha has been shown to potentiate cisplatin and other drugs experimentally and in clinical trials involving NSCLC. We are looking at the responses of different NSCLC cell lines to cisplatin (P), etoposide (VP-16) and IFN [recombinant human IFN-alpha 2c (IFN-alpha) and IFN-gamma 1b (IFN-gamma)], individually and in combination. We then compare the results with those from a clinical trial of etoposide and cisplatin with interferon in advanced NSCLC. We report here the results from the first of our cell lines, established from a large cell anaplastic carcinoma. We have confirmed earlier findings that NSCLC cell lines are not sensitive to either IFN-alpha or IFN-gamma alone. However a combination of IFN-alpha and IFN-gamma does reduce cell proliferation in our cell lines. This IFN combination potentiates the response of the cells to etoposide far more than to cisplatin. There is a trend towards greater activity when a combination of cisplatin and etoposide is used, compared with the activity of either drug alone. This effect is further increased by the interferon combination.

Mesothelioma is a tumor of the serous surfaces in the thorax and abdomen. This tumor has proved to be exceptionally resistant to treatment, although a variety of multi-modality therapies have been tried. We have used four human mesothelioma cell lines, originating from diffuse asbestos-related malignant (pleural) mesothelioma, to assess in vitro sensitivity to five chemotherapeutic drugs, to recombinant human interferon (IFN)-alpha and -gamma and to combined immuno-chemotherapy. The cytotoxic effects were assayed by vital dye exclusion. The drugs tested were etoposide, cisplatin, mitoxantrone, 4-epirubicin and vindesine. The combinations tested were etoposide+cisplatin, and etoposide+cisplatin+mitoxantrone. All the drugs and combinations were also tested with recombinant human (rHu) IFN-alpha 2C (rHuIFN-alpha), rHuIFN-gamma, and rHuIFN-alpha+rHuIFN-gamma. The cell lines were most sensitive to mitoxantrone, 4-epirubicin and vindesine (TC50 < or = 0.001 micrograms/ml), and least sensitive to etoposide and cisplatin (TC50 > or = 0.1 micrograms/ml) used singly. There was no improvement in sensitivity when the drugs were combined. To further investigate the lack of response to cisplatin treatment, we examined the binding of cisplatin to the mesothelioma cell DNA. The tumor cell DNA bound markedly less cisplatin than human fetal fibroblast DNA. Three cell lines were tested with rHuIFN-alpha and rHuIFN-gamma on their own or rHuIFN-alpha+rHuIFN-gamma. They were consistently sensitive to rHuIFN-alpha, but the sensitivity to rHuIFN-gamma varied with the cell lines. Finally, we tested two cell lines with the drugs singly and in combination, together with 0.01 micrograms/ml each of rHuIFN-alpha and rHuIFN-gamma.(ABSTRACT TRUNCATED AT 250 WORDS)