Immune-dependent distant bystander effect after adenovirus-mediated suicide gene transfer in a rat model of liver colorectal metastasis.

Gene transfer of the herpes simplex virus thymidine kinase (HSV-tk) gene sensitizes tumor cells to the toxic effect of ganciclovir (GCV). The toxic effect of GCV extends to nontransduced surrounding cells by a metabolic process known as the bystander effect. A distant bystander effect, which involves anatomically separated tumors, has been reported in vivo. Our aim was to evaluate and characterize such distant effect in a rat model of colorectal tumors implanted in the liver using adenovirus to carry the HSV-tk gene. Two colorectal tumors were implanted in two distinct liver lobes of the liver. One of the tumor was transduced with an adenoviral vector containing HSV-tk gene. The volumes of the tumors were monitored after GCV treatment. Implication of the immune system was studied histologically and after in vivo manipulations. After GCV administration, the nontransduced distant tumor regressed partially or completely in the experimental group. Immunohistochemical analysis revealed the presence of CD8+ lymphocytes in the distant lesion. HSV-tk/GCV-induced immune response against tumors was evidenced by an adoptive transfer assay (Winn assay) and the distant bystander effect was blunted after CD8+ lymphocytes depletion. However, the survival rates for treated animals were not improved. These findings demonstrate that an immune-mediated effective distant bystander effect can be obtained after limited adenoviral-mediated transfer of the HSV-tk gene.

Docetaxel (Taxotere) - an update.

The development of docetaxel, a member of the taxoid family, has been recent and rapid. Phase I studies recommend that a dose of 100 mg/m(2) be administered every three weeks in a 1-h infusion. These studies have also demonstrated that the major dose-limiting toxicity is neutropenia. Major clinical research projects are now being carried out for breast cancer, non-small-cell lung cancer (NSCLC), squamous cell carcinoma of the head and neck (SCCHN) and gastric cancer. In advanced and metastatic NSCLC, Phase II studies have shown a response rate of 30 - 40%, and responses have been obtained in cis-platinum failures. In advanced and metastatic breast cancer, first-line treatment has yielded a response rate of 54 - 68%, and the rate for second-line response is only slightly lower, indicating an absence of cross-resistance. Phase II combination studies with docetaxel are in progress, and preliminary results are promising. The first Phase III study demonstrated preliminary response rates significantly higher than seen with doxorubicin, although survival data have not yet been published. Fewer results are available from SCCHN studies, but response rates have been encouraging (around 40%). Although further long-term data are needed to determine the precise role of docetaxel in combination with other drugs, it is apparent that this promising drug shows one of the best response rates for monotherapy in NSCLC and breast cancer.