Reference

In vivo chemosensitization by misonidazole in sensitive and resistant tumor lines

In vivo chemosensitization by misonidazole in sensitive and resistant tumor lines. Mulcahy, R. Timothy; Siemann, Dietmar W. (Cancer Cent., Univ. Rochester, Rochester, NY 14642, USA). Cancer Res., 43(10), 4709-13 (English) 1983. CODEN: CNREA8. ISSN: 0008-5472. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacology) Section cross-reference(s): 8 Misonidazole (MISO) (I) [13551-87-6] [5.0 mmol/kg (1.0 mg/g)] potentiated the response of the parenteral nitrosourea-sensitive L1210/0 tumor to a 20-mg/kg dose of CCNU [13010-47-4] in mice. When combined with doses of CCNU <20 mg/kg or with BCNU [154-93-8], MISO failed to modify the response of the L1210/0 tumor. Significant chemosensitization also was evident when 2.5- and 1.25-mmol/kg doses of MISO were used in combination with CCNU at 20 mg/kg. The effectiveness of BCNU and CCNU against the nitrosourea-resistant L1210/BCNU tumor was not improved by MISO (5. 154-93-8 and 13551-87-6 which are cas registry numbers of substances are two of reagents here.0 mmol/kg), even when the sensitizer was combined with doses of nitrosoureas approaching the 10% LD (60 days). In contrast, the effectiveness of CCNU against the parental KHT and resistant KHT/CCR tumors, assessed by a tumor regrowth assay, was equally enhanced by simultaneous MISO treatment. Therefore, one cannot safely predict the extent of enhancement which might result from the addn. of MISO to a chemotherapeutic regimen, based solely on the responsiveness of the tumor to the chemotherapy drug(s) alone. .

Effects of carbamoylation on cell survival and DNA repair in normal human embryo cells (IMR-90) treated with various 1-(2-chloroethyl)-1-nitrosoureas

Effects of carbamoylation on cell survival and DNA repair in normal human embryo cells (IMR-90) treated with various 1-(2-chloroethyl)-1-nitrosoureas. Sariban, Eric; Erickson, Leonard C.; Kohn, Kurt W. (Div. Cancer Treat., Natl. Cancer Inst., Bethesda, MD 20205, USA). Cancer Res., 44(4), 1352-7 (English) 1984. CODEN: CNREA8. ISSN: 0008-5472. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacology) The possibility was examd. that the carbamoylating activity of some chloroethylnitrosoureas could interfere with the ability of normal human cells to survive treatment with these drugs; 1-(2-chloroethyl)-3-(trans-4-hydroxycyclohexyl)-1-nitrosourea [56239-24-8], which has strong carbamoylating activity, inhibited the rejoining of drug- or x-ray-induced DNA strand breaks in IMR-90 cells, whereas the noncarbamoyling cis-2-hydroxy isomer [66052-62-8] had little or no effect; 1-(2-chloroethyl)-3-(trans-4-hydroxycyclohexyl)-1-nitrosourea was twice as potent as the cis-2-hydroxy isomer in reducing colony survival. The moderately or highly carbamoylating drugs 1,3-bis(2-chloroethyl)-1-nitrosourea [154-93-8] and 1-(2-chloroethyl)-3-(cyclohexyl)-1-nitrosourea [13010-47-4] had effects resembling those of 1-(2-chloroethyl)-3-(trans-4-hydroxycyclohexyl)-1-nitrosourea. The poorly carbamoylating drug 1-(2-chloroethyl)-3-(2,6-dioxo-1-piperidyl)-1-nitrosourea [13909-02-9] had effects resembling those of the cis-2-hydroxy isomer. 56239-24-8 and 13909-02-9 are also in the experiment. 1-(2-Chloroethyl)-1-nitrosourea [2365-30-2], although a strong carbamoylator in chem. systems, behaved biol. as if it were a low carbamoylator. This can be rationalized on the basis of limited cellular uptake of cyanate ion. The results suggest that carbamoylation may inhibit the nucleotide excision repair of chloroethylnitrosourea-induced DNA damage that may be crucial to the ability of normal human cells to recover from the action of these drugs. Previous work has indicated that susceptible human tumor cells are sensitive to chloroethylnitrosoureas because of a lack of a DNA repair protein (guanine O6-alkyltransferase) that is not involved in nucleotide excision repair. On the basis of these findings and other evidence, further clin. trials of appropriate noncarbamoylating chloroethylnitrosoureas would be justified. .