brivudine and Colonic-Neoplasms

The phosphoramidate technology we have developed has been recently applied to BVdU, leading to NB1011 (NewBiotics Inc., California), a novel potential anticancer compound recently entered into phase 2 of the clinical trials for colon cancer. We report in this work a new series of derivatives containing naphthol as aryl masking group on the phosphate moiety, which has shown a significant increase in anticancer activity in preliminary biological evaluations.

Topics: Amides; Antineoplastic Agents; Antiviral Agents; Bromodeoxyuridine; Cell Line, Tumor; Colonic Neoplasms; Female; Humans; Male; Models, Chemical; Phosphoric Acids

Metabolic suicide gene transfer is widely applied for gene therapy of cancer, and retroviral vectors expressing the herpes simplex virus thymidine kinase (HSV-tk) gene are commonly used in clinical trials. Most of these vectors contain positive selectable markers that undoubtedly facilitate the determination of viral titer and the identification of high-titer producer clones. However, the presence of additional transcriptional units may result in reduced expression of the gene of interest. The use of fusion genes expressing bifunctional proteins may help to overcome this problem. We have constructed a retroviral vector carrying the TNFUS69 chimeric gene, which originates from the fusion of the HSV-tk and neomycin phosphotransferase II genes, and evaluated the functional expression of the encoded fusion protein. In vitro, expression of the fusion gene conferred to target cells both resistance to neomycin and selective sensitivity to the antiherpetic drugs ganciclovir and (E)-5-(2-bromovinyl)-2'-deoxyuridine. Cells transduced with the fusion gene, however, showed reduced ability to phosphorylate ganciclovir compared with cells expressing the native HSV-tk. Therefore, although the fusion gene may be used as a constituent of retroviral cassettes for positive and negative selection in vitro, its usefulness for suicide gene transfer applications in vivo may depend upon the possibility of using (E)-5-(2-bromovinyl)-2'-deoxyuridine in a clinical context.

Topics: 3T3 Cells; Adenocarcinoma; Animals; Antiviral Agents; Bromodeoxyuridine; Colonic Neoplasms; Fibrosarcoma; Ganciclovir; Genetic Vectors; Kanamycin Kinase; Mice; Mice, Inbred C57BL; Phosphorylation; Plasmids; Recombinant Fusion Proteins; Retroviridae; Simplexvirus; Thymidine Kinase; Transcription, Genetic; Transfection; Tumor Cells, Cultured

The goal of this study was to improve the therapeutic index of the herpes simplex virus-thymidine kinase/ganciclovir (HSV-tk/GCV) system by the addition of thymidylate synthase (TS) inhibitors. For this, we assessed the potential of GCV to synergistically interact with 5-fluorouracil (5-FU), ZD1694 (Tomudex), and (E)-5-(2-bromovinyl)-2'-deoxyuridine in HSV-tk-expressing murine MC38 STK and human HT-29 STK colon carcinoma cell lines. Synergistic cell killing was observed in a clonogenic assay over most of the cytotoxic dose range by the median-effect principle of Chou and Talalay (T. C. Chou and P. Talalay, Adv. Enzyme Regul., 22: 27-55, 1984). In a s.c. HT-29 STK xenograft tumor model, we demonstrated that the combination of GCV and 5-FU resulted in statistically significant enhanced animal survival over single-agent treatment. Furthermore, we showed that the combination of GCV and ZD1694 in association with the HSV-tk/GCV system was at least as effective as GCV/5-FU in vitro and in vivo. The mechanism for the observed synergy is most likely attributable to the increased GCV phosphorylation in the presence of the tested TS inhibitors. Our data suggest that the HSV-tk/GCV metabolic suicide gene transfer system could serve as an adjuvant of the presently used TS inhibitors, thus potentially improving the efficacy of present cancer gene therapy approaches.

Topics: Antiviral Agents; Bromodeoxyuridine; Colonic Neoplasms; Combined Modality Therapy; Enzyme Inhibitors; Fluorouracil; Ganciclovir; Genetic Therapy; Humans; Quinazolines; Simplexvirus; Thiophenes; Thymidine Kinase; Thymidylate Synthase; Tumor Cells, Cultured; Tumor Stem Cell Assay

The antitumor activity of 5'-deoxy-5-fluorouridine (DFUR), a prodrug of 5-fluorouracil (5-FU), is markedly enhanced if DFUR treatment is combined with (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU). Combined oral administration of DFUR (10 mg/kg) and BVDU (10 mg/kg) three times (every 3 h) per day for 5 days afforded greater antitumor activity than a single dose of DFUR (300 mg/kg/day) for 5 days in mice bearing either adenocarcinoma 755 or Lewis lung carcinoma, while in the colon 26 system the antitumor effects of both treatment regimens were equivalent. Thus, a low-dose regimen of DFUR when combined with BVDU provides a similar or greater antitumor activity than a high-dose regimen of DFUR that is not combined with BVDU. The area under the curve of plasma 5-FU following a treatment with the combination of DFUR (10 mg/kg) and BVDU (10 mg/kg) was equal to that following DFUR (300 mg/kg) treatment.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Antiviral Agents; Bromodeoxyuridine; Colonic Neoplasms; Drug Therapy, Combination; Floxuridine; Fluorouracil; Liver Neoplasms; Lung Neoplasms; Mice; Mice, Inbred BALB C; Pentosyltransferases; Prodrugs; Pyrimidine Phosphorylases