Abstract
In HT29 cells 5-fluorouracil (5FU) cytotoxicity is enhanced by subsequent incubation of cells in medium containing 1% N-methylformamide (NMF). This enhancement does not appear to be related to differences in the repair of 5FU-induced DNA damage. It is proposed that the inhibition of DNA synthesis by NMF (that is reversible and does not result in any detectable toxicity) becomes a lethal event in a cell in which DNA synthesis has already been altered by 5FU exposure. The synergism is sequence dependent (i.e. it does not occur when NMF is given before 5FU) and specific for some cell types as shown by the fact that no synergism was found in L1210 mouse leukaemia cells. In nude mice transplanted s.c. with HT29 cells daily 5FU treatment (for 5 days) followed by daily NMF treatment (for 10 days) caused much greater inhibition of tumour growth than either drug alone or the same combination given in the opposite order (NMF then 5FU). These results, if confirmed on other human colon tumours, could be of clinical interest as a means of increasing the therapeutic efficacy of 5FU in patients with colon cancer.
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Selected References
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- Bill C. A., Gescher A., Hickman J. A. Effects of N-methylformamide on the growth, cell cycle, and glutathione status of murine TLX5 lymphoma cells. Cancer Res. 1988 Jun 15;48(12):3389–3393. [PubMed] [Google Scholar]
- Dexter D. L., Lee E. S., Bliven S. F., Glicksman A. S., Leith J. T. Enhancement by N-methylformamide of the effect of ionizing radiation on a human colon tumor xenografted in nude mice. Cancer Res. 1984 Nov;44(11):4942–4946. [PubMed] [Google Scholar]
- Harpur E. S., Langdon S. P., Fathalla S. A., Ishmael J. The antitumour effect and toxicity of cis-platinum and N-methylformamide in combination. Cancer Chemother Pharmacol. 1986;16(2):139–147. doi: 10.1007/BF00256164. [DOI] [PubMed] [Google Scholar]
- Krishan A., Frei E., 3rd Effect of adriamycin on the cell cycle traverse and kinetics of cultured human lymphoblasts. Cancer Res. 1976 Jan;36(1):143–150. [PubMed] [Google Scholar]
- Langdon S. P., Hickman J. A. Alkylformamides as inducers of tumour cell differentiation--a mini-review. Toxicology. 1987 Mar;43(3):239–249. doi: 10.1016/0300-483x(87)90083-7. [DOI] [PubMed] [Google Scholar]
- Langdon S. P., Hickman J. A., Gescher A., Stevens M. F., Chubb D., Vickers L. M. N-Methylformamide (NSC 3051): a potential candidate for combination chemotherapy. Eur J Cancer Clin Oncol. 1985 Jun;21(6):745–752. doi: 10.1016/0277-5379(85)90273-1. [DOI] [PubMed] [Google Scholar]
- Leith J. T., Lee E. S., Leite D. V., Glicksman A. S. Enhanced X ray sensitivity of human colon tumor cells by combination of N-methylformamide with chemotherapeutic agents. Int J Radiat Oncol Biol Phys. 1986 Aug;12(8):1423–1427. doi: 10.1016/0360-3016(86)90186-0. [DOI] [PubMed] [Google Scholar]
- Leith J. T., Lee E. S., Vayer A. J., Jr, Dexter D. L., Glicksman A. S. Enhancement of the responses of human colon adenocarcinoma cells to X-irradiation and cis-platinum by N-methylformamide (NMF). Int J Radiat Oncol Biol Phys. 1985 Nov;11(11):1971–1976. doi: 10.1016/0360-3016(85)90279-2. [DOI] [PubMed] [Google Scholar]
- Lorico A., Toffoli G., Boiocchi M., Erba E., Broggini M., Rappa G., D'Incalci M. Accumulation of DNA strand breaks in cells exposed to methotrexate or N10-propargyl-5,8-dideazafolic acid. Cancer Res. 1988 Apr 15;48(8):2036–2041. [PubMed] [Google Scholar]
- Lotan R., Nicolson G. L. Can anticancer therapy be improved by sequential use of cytotoxic and cytostatic (differentiating or immunomodulating) agents to suppress tumor cell phenotypic diversification? Biochem Pharmacol. 1988 Jan 15;37(2):149–154. doi: 10.1016/0006-2952(88)90711-3. [DOI] [PubMed] [Google Scholar]
- Lönn U., Lönn S. DNA lesions in human neoplastic cells and cytotoxicity of 5-fluoropyrimidines. Cancer Res. 1986 Aug;46(8):3866–3870. [PubMed] [Google Scholar]
- Lönn U., Lönn S. Interaction between 5-fluorouracil and DNA of human colon adenocarcinoma. Cancer Res. 1984 Aug;44(8):3414–3418. [PubMed] [Google Scholar]
- Major P. P., Egan E., Herrick D., Kufe D. W. 5-Fluorouracil incorporation in DNA of human breast carcinoma cells. Cancer Res. 1982 Aug;42(8):3005–3009. [PubMed] [Google Scholar]
- Yoshioka A., Tanaka S., Hiraoka O., Koyama Y., Hirota Y., Ayusawa D., Seno T., Garrett C., Wataya Y. Deoxyribonucleoside triphosphate imbalance. 5-Fluorodeoxyuridine-induced DNA double strand breaks in mouse FM3A cells and the mechanism of cell death. J Biol Chem. 1987 Jun 15;262(17):8235–8241. [PubMed] [Google Scholar]
- Zupi G., Marangolo M., Arancia G., Greco C., Laudonio N., Iosi F., Formisano G., Malorni W. Modulation of the cytotoxic effect of 5-fluorouracil by N-methylformamide on a human colon carcinoma cell line. Cancer Res. 1988 Nov 1;48(21):6193–6200. [PubMed] [Google Scholar]
