Fused pyrazine mono-n-oxides as bioreductive drugs. II Cytotoxicity in human cells and oncogenicity in a rodent transformation assay
| Autor: | Tom K. Hei, Robert M. Sutherland, Su-Xian Liu, Keith R. Laderoute, Eric J. Hall, Virginia K. Langmuir, Gerald E. Adams, Holly L. Mendonca, Matthew A. Naylor |
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| Rok vydání: | 1996 |
| Předmět: |
Cancer Research
Antineoplastic Agents Oncogenicity medicine.disease_cause Mice Structure-Activity Relationship In vivo medicine Tumor Cells Cultured Structure–activity relationship Animals Humans Radiology Nuclear Medicine and imaging Clonogenic assay Cytotoxicity Mice Inbred C3H Radiation Dose-Response Relationship Drug business.industry Radiobiology In vitro Cell Hypoxia Cell Transformation Neoplastic Oncology Mechanism of action Biochemistry Pyrazines Immunology medicine.symptom Drug Screening Assays Antitumor business HT29 Cells Genotoxicity |
| Zdroj: | International journal of radiation oncology, biology, physics. 34(1) |
| ISSN: | 0360-3016 |
| Popis: | Purpose:To determine what structural moieties of the fused pyrazine mono-N-oxides are determining factors in their in vitro cytotoxicity and oncogenicity. Methods and Materials:A new series of experimental bioreductive drugs, fused pyrazine mono-N-oxides, was evaluated in vitro for aerobic and hypoxic cytoxicity in the HT29 human colon adenocarcinoma cell line by using clonogenic assays. The relative oncogenecities of these compounds were also determined in aerobic cultures of C3H 10T1/2 mouse embryo fibroblasts by using a standard transformation assay. Results: Removal of the 4-methyl piperazine side chain from the parent compound, RB 90740, reduced the potency of the hypoxic cytotoxin. Reduction of the N-oxide function increased the aerobic cytotoxicity and eliminated most of the hypoxic/aerobic cytotoxic differential. The reduced N-oxide also had significant oncogeneity, consistent with a mechanism of genotoxicity following bioreduction of RB 90740. Conclusion: This new series of bioreductive compounds may be effective in cancer therapy, particularly the lead compound RB 90740. The oncogenic potential of these compounds is similar to that for other cancer therapies. Further studies should include evaluation of these compounds in vivo and the development of analogs with reduced oncogenic potential and retention of the hypoxic/aerobic cytoxicity differential. |
| Databáze: | OpenAIRE |
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