Curative Potential of Herpes Simplex Virus Thymidine Kinase Gene Transfer in Rats with 9L Gliosarcoma

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Abstract
The transfer of the gene coding for the thymidine kinase of the herpes simplex virus (HSV-tk), followed by ganciclovir (GCV) administration, has been described for the treatment of several types of cancer, especially brain tumors. We further studied the efficacy of this approach by using the 9L rat gliosarcoma model, and cells producing 5 × 103, 9 × 104, 3 × 105 HSV-tk retroviral particles per milliliter. Their stereotactic injection in 9L brain tumors and GCV treatment did not result in any increase of survival. To study a model of optimal in vivo transduction, we examined the survival of rats with tumors growing from 9L cells that had been previously transduced in vitro with the HSV-tk vectors (9LTk cells). We observed that GCV administration cured 26% (n = 42) of the animals with 9LTk brain tumors, with most of the relapsing tumors remaining HSV-tk positive. The increase of either the dose or the duration of GCV treatment did not improve the survival rate. But the cerebral localization of the tumor played an important role, because this survival rate reached 67% (n = 12) when similar tumors were growing subcutaneously. No or only marginal antitumoral responses were induced by the presence of a selectable marker gene in the HSV-tk vectors. These results demonstrate that in vitro HSV-tk gene transfer in 9L tumor cells, but not in vivo gene transfer, followed by GCV treatment, is able to cure rats at a rate that is higher for subcutaneous than for intracerebral tumors. While some studies reported the therapeutic efficacy of herpes simplex virus thymidine kinase (HSV-tk) gene transfer, followed by ganciclovir (GCV) administration, for the treatment of cancer, other studies showed rapid relapses at the end of GCV administration or questioned the validity of this approach. Using the same experimental conditions and vectors as the NIH group, as well as vectors with high titers, this study showed that long-term survival of rats with 9L tumors was observed only in animals with tumors that had been transduced in vitro, but not with tumors transduced in vivo. The results also demonstrated that 9LTk subcutaneous tumors are treated more efficiently than brain tumors, which might be related to the generation of more effective antitumoral immune responses when the tumors were subcutaneous. The presence of a selectable marker gene and of the HSV-tk gene in the viral particles did not induce, by themselves, major antitumoral responses.

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