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Abstract for TR-57 - beta-2'-deoxy-6-thioguanosine monohydrate (b-TGdR) (CASRN 789-61-7)

Abstract

Bioassay of b-TGdR for Possible Carcinogenicity (CAS No. 789-61-7)

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Chemical Formula: C10H13N5O3S

Beta-2'-deoxy-6-thioguanosine monohydrate (b-TGdR) is an experimental anticancer drug and a derivative of the anticancer drug 6-thioguanine (6-TG).

A bioassay of beta-2'-deoxy-6-thioguanosine monohydrate (b-TGdR) for possible carcinogenicity was conducted by administering the test chemical by intraperitoneal injection to Sprague-Dawley rats and B6C3F1 mice.

Groups of 35 rats of each sex were administered b-TGdR in a buffered saline and polysorbate 80 vehicle at one of two doses, either 3.5 or 7 mg/kg body weight, three times per week for 52 weeks, then observed for an additional 26 weeks. Controls consisted of groups of 10 rats of each sex, which were either administered the vehicle alone (matched vehicle controls) or were untreated (matched untreated controls). Pooled controls consisted of the matched vehicle controls of each sex from the current bioassay, combined with 20 corresponding vehicle controls of each sex from similar bioassays of two other test chemicals. All surviving rats were killed at 78 or 79 weeks.

Groups of 35 mice of each sex were administered the chemical in a buffered saline and polysorbate 80 vehicle at one of two doses, either 2 or 4 mg/kg, three times per week for 52 weeks, then observed for periods of up to 27 weeks, depending on length of survival. Because of severe toxicity at the high dose, resulting in loss of all mice by week 12 (males) or week 25 (females), additional groups of 35 mice of each sex were administered 1 mg/kg on the same schedule. Controls consisted of groups of 15 mice of each sex, which were either administered the vehicle or were untreated. Pooled controls consisted of groups of 15 vehicle-control animals of each sex from studies using the doses of 2 or 4 mg/kg, combined with corresponding groups of 15 vehicle-control animals of each sex from the study using the dose of 1 mg/kg.

b-TGdR was toxic to rats at the doses used in this study. Mean body weights of the high- and low-dose rats of both sexes were lower than those of the corresponding vehicle controls throughout the study. There was also severe early mortality in the high-dose groups of both sexes and positive dose-related trends in mortality over the period of the bioassay. However, 66% of the low-dose males and 77% of the low-dose females survived until termination of the study.

In mice, b-TGdR was toxic at the doses originally selected. Mean body weights were not consistently affected; however, at the high dose only three males and seven females lived past week 7, and all were dead by week 25. In the mid-dose group, only 14% of the males and 6% of the females survived until termination of the study at week 79; in the low-dose group, the survival rate was 31% for the males and 29% for the females.

Because of the high mortality, time-adjusted statistical analyses were performed for both rats and mice.

In rats, the incidence of carcinomas of the ear canal (combined carcinomas and squamous-cell carcinomas) was statistically significant in both sexes. In males, the results of the test for dose-related trend were significant using either matched vehicle (P=0.046) or pooled vehicle (P=0.014) controls, but direct comparisons of dosed male rats with matched vehicle or pooled vehicle controls did not show significant differences (matched vehicle controls 0/10, pooled vehicle controls 0/28, low-dose 1/31, high-dose 2/7). In females, the results of the test for dose-related trend were significant using either matched vehicle (P=0.002) or pooled vehicle (P<0.001) controls, and the incidence in the high-dose group was significantly higher than that in either the matched vehicle (P=0.023) or pooled vehicle (P<0.001) controls (matched vehicle controls 0/9, pooled vehicle controls 0/28, low-dose 2/32, high-dose 6/13). There were no such ear canal tumors among 165 historical vehicle controls of either sex or among 220 female untreated controls at the laboratory, and only two such tumors occurred among 215 male untreated controls.

In mice, no tumors appeared in statistically significant incidences in the dosed groups compared with the matched vehicle controls, and there was no significant evidence of dose-related trend for any tumors. The incidences of the combination of lymphoma and leukemia were significantly higher in the matched vehicle controls of each sex than in the corresponding matched untreated controls (males: matched untreated controls 1/30, matched vehicle controls 19/29; females: matched untreated controls 2/30, matched vehicle controls 21/29). This high incidence in the matched vehicle controls may have been due to a systematic procedural problem associated with injection of the drug.

It is concluded that under the conditions of this bioassay, the low survival of the dosed and vehicle-control groups of mice, as well as the possible procedural problem that may have affected the incidences of tumors in these groups, does not allow a determination to be made of the carcinogenic potential of b-TGdR in this species. b-TGdR in the vehicle of 0.05% polysorbate 80 was, however, carcinogenic in rats, producing carcinomas of the ear canal in the females and possibly also in the males.

Levels of Evidence of Carcinogenicity:

Male Rats: Equivocal
Female Rats: Positive
Male Mice: Inadequate
Female Mice: Inadequate


Report Date: 1978

Target Organs from 2-year Studies


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