| Metastatic colon carcinoma is the second leading cause of death from malignancy in the United States, and development of more effective treatments is essential. Heterologous expression of Herpes Simplex Virus Thymidine Kinase (HSVtk) in combination with the prodrug, ganciclovir (GCV), has shown great promise for the genetic therapy of many cancers, but most patients have had only a partial or minimal response to the therapy. After screening a panel of two drug combinations, our laboratory has shown that the combination of GCV and the protein kinase inhibitor UCN-01 (7-hydroxystaurosporine) enhances tumor cell death more effectively than either drug alone. However the molecular basis of this enhancement was unknown, and it was investigated by studying the effects on the cell cycle, DNA metabolism and damage signaling, and finally tested in the transgenic adenocarcinoma of mouse prostate (TRAMP) model. Colon tumor cells treated with GCV arrest in S-phase, and cells treated with the combination of UCN-01 and GCV also undergo S-phase specific cell death. However, UCN-01 treatments induced the disappearance of key mitotic proteins and had variable effects on the cell cycle. |
