PubMed · 11686014
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Y Nieto, R B Jones. 2001. DNA-binding agents.. https://pubmed.ncbi.nlm.nih.gov/11686014/
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Triazenes (RN=N-NR'R") are a class of compounds that hold much promise in preparative chemistry as they are reactive groups which are both stable and adaptable to numerous synthetic transformations. Useful to scientists in pharmacology, total synthesis, polymer technology, and the construction of novel ring systems, to name a few areas, triazenes also have a tendency to surprise chemists with new reactions and increasing applicability. This review highlights some of the recent advances and diversity possible with these types of systems.
BACKGROUND: Herpes simplex virus 1 (HSV-1) infection of cancer cells results in viral replication with cell destruction and liberation of progeny virion that infect adjacent tumor cells. rRp450 is a novel replication-conditional HSV-1 mutant that expresses both the endogenous herpes viral thymidine kinase gene and the rat p450 CYP2B1 transgene; p450 bioactivates such cancer prodrugs as cyclophosphamide. METHODS: Viral cytotoxicity and replication assays were performed in colon carcinoma cells as well as primary human hepatocytes. For in vivo studies, diffuse liver metastases were generated by inoculating MC26 cells into the portal system of BALB/c mice. Mice were treated with control media, rRp450, or rRp450 plus cyclophosphamide. RESULTS: Cytopathic effects induced by rRp450 replication in colon carcinoma cells were equivalent to those induced by wild type HSV-1 in vitro. Assays developed to separate cytotoxicity mediated by viral replication from cytotoxicity mediated by chemotherapy confirmed that HSV-1 thymidine kinase bioactivates ganciclovir and CYP2B1 bioactivates cyclophosphamide in rRp450-infected cells. rRp450 mediated cytotoxicity in the presence of cyclophosphamide was increased by 21% to 30% above that achieved by viral replication alone. Cyclophosphamide bioactivation produced bystander killing of colon carcinoma cells but not hepatocytes. In contrast to these effects of cyclophosphamide, rRp450 mediated cytotoxicity was reduced in the presence of ganciclovir. These findings are explained by further experiments showing that bioactivation of cyclophosphamide only minimally affected HSV-1 replication in colon carcinoma cells, whereas bioactivation of ganciclovir markedly attenuated HSV-1 replication. In vivo studies revealed a substantial decrease in hepatic tumor burden in all rRp450-treated animals compared to controls. The addition of cyclophosphamide augmented rRp450's in vivo anti-neoplastic effect. CONCLUSIONS: The rRp450 mutant HSV-1 is highly oncolytic against colon carcinoma cells both in vitro and in vivo. rRp450 displays preferential replication in colon carcinoma cells compared to normal hepatocytes. Activation of cyclophosphamide by the p450 transgene augmented the anti-neoplastic effects of rRp450 without simultaneously decreasing viral replication. Oncolysis induced by HSV-1 replication combined with cyclophosphamide prodrug activation warrants further investigation as a potential therapy for colon carcinoma liver metastases.
PURPOSE: Highly 5-HT(3)-receptor-specific antiemetic agents may have different effects on ion transport of tumour cells during treatment with cytotoxic drugs. Cell volume regulation, which is dependent on potassium ion (K(+)) flux, is involved the control of cell growth, proliferation, and apoptosis. K(+)-flux response mechanisms to the antiemetics ondansetron and granisetron were therefore correlated to malignant glioma cell (Mg251) volume response to estramustine phosphate (EMP) in vitro. METHODS: We quantified the influx and efflux of potassium ions (using the K(+) analogue (86)Rb(+)) as well as cell volume changes (with image analysis) of glioma cells incubated with the 5-HT(3)-receptor antagonists ondansetron and granisetron (0.1 micro mol/l) combined with 40 mg/l EMP. RESULTS: The EMP-induced cell volume increase was fully inhibited by ondansetron but not affected by granisetron. Ondansetron retained high cellular K(+)-efflux and reduced Na(+), K(+), 2Cl(-)-cotransport activity, whereas granisetron (0.1 micro mol/l) reduced K(+)-efflux and retained an augmented Na(+), K(+), 2Cl(-)-cotransport activity in the presence of 40 mg/l EMP. CONCLUSIONS: Ondansetron affects K(+) transport with ensuing effects on cell volume of tumour cells treated with EMP, whereas granisetron does not. Since ondansetron and other 5-HT(3)-receptor antagonists are used routinely to prevent nausea during anticancer treatment, an increased awareness of possible interactions with the antitumour efficacy of anticancer drugs seems warranted.