Cyclosporin A enhances paclitaxel toxicity against leukemia and respiratory epithelial cancers.

Multidrug resistance is probably the single greatest obstacle to successful systemic therapy of human cancer. We have reported that cyclosporin A (CsA) can overcome multidrug resistance and improve the efficacy of etoposide in a murine model of drug-sensitive leukemia. The combination of CsA and paclitaxel (PCL) was also significantly superior to either drug alone against murine P388 (sensitive) and L1210 (resistant) leukemia. Lung cancer cells provide an ideal model system to study this phenomenon because both de novo and acquired drug resistance occur. Standard chemotherapy for advanced lung cancer is poorly effective, and although PCL is one of the most active new agents for this disease, responses occur in only 20% of patients. In vitro, CsA significantly enhanced the efficacy of PCL against lung (Lu-CSF-1 and 3LL) and oropharyngeal (CSCC-20) cancer cell lines. The combination also produced an increase in expression of interleukin 1beta, a cytokine known to inhibit the growth of Lu-CSF-1 cells. CsA alone had little or no antiproliferative activity in vitro and did not alter PCL transport. These results indicate that the activity of chemotherapy modulators may extend beyond mitigation of drug resistance to enhancement of therapeutic efficacy against drug-sensitive tumor cells in vitro and in vivo.

High and low dose rate irradiation have opposing effects on cytokine gene expression in human glioblastoma cell lines.

Effects of radiation on five cytokine expressing human glioblastoma cell lines were studied. In comparison to unirradiated controls, IL-1 beta and IL-6 mRNAs were generally reduced after low (LDR, 1.0 cGy/min) and very low (VLDR, 0.35 cGy/min) dose rate irradiation. In contrast, high (HDR, 200 cGy/min) and intermediate (IDR, 4.1 cGy/min) dose rates increased steady-state levels of IL-1 beta and IL-6 mRNAs. The surviving fraction was generally inversely proportional to the dose rate; however, these glioma cells were unusually susceptible to LDR. In the two cell lines tested, IDR was less cytotoxic than either HDR or LDR irradiation. Although cytokine gene expression had no clear effect on radiation survival in vitro, autologous cytokines could be important to radiation response in vivo by affecting immune response, tumour stroma, vasculature or surrounding tissues. Adjusting dose rates to account for inverse dose rate effects and altered gene expression may be a useful strategy in optimising radiation therapy of glioblastomas.