Bioassay of Acronycine for Possible Carcinogenicity
(CAS No. 7008-42-6)
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Chemical Formula: C20H19NO3
Acronycine, an alkaloid derived from the bark of the Australian scrub ash, has been investigated as an experimental anticancer drug. Acronycine was selected for screening in the carcinogenesis program in an attempt to evaluate the carcinogenicity of certain drugs that may be used for prolonged periods in humans.
A bioassay of acronycine for possible carcinogenicity was conducted by administering the test chemical by intraperitoneal injection to Sprague-Dawley rats and B6C3F1 mice.
Initially, groups of 35 rats of each sex were administered acronycine at one of two doses, either 7.5 or 15 mg/kg body weight, in a vehicle composed of 0.05% polysorbate 80 in phosphate-buffered saline. Control groups of each sex consisted of 10 untreated rats (untreated controls) and 10 rats injected with the vehicle (vehicle controls). Because of high mortality rates in the dosed animals, new dosed groups of 35 rats of each sex were started later at a dose of 3.75 mg/kg. Additional groups of 10 untreated and 10 vehicle controls of each sex were also started. The rats were administered the acronycine or the vehicle for 51 or 52 weeks, then observed for an additional 28-30 weeks. All surviving rats were killed at 80-82 weeks.
Initially, groups of 35 mice of each sex were administered acronycine at one of two doses, either 12.5 or 25 mg/kg body weight, in a vehicle composed of 0.05% polysorbate 80 in phosphate-buffered saline. Control groups of each sex consisted of 10 untreated mice (untreated controls) and 10 mice injected with the vehicle (vehicle controls). Because of high mortality rates in the dosed animals, two additional dosed groups were started later: 35 mice of each sex at 6 mg/kg and 40 mice of each sex at 2 mg/kg, together with 10 untreated controls and 10 vehicle controls of each sex for the groups dosed at 6 mg/kg, and 20 untreated controls and 20 vehicle controls for the groups dosed at 2 mg/kg. Periods of administration of the chemical to the mice varied from 25 weeks to 92 weeks, depending on toxicity or length of time of survival. Surviving control animals were killed at 78-105 weeks.
Acronycine was toxic to rats and mice of each sex at the doses used in this bioassay, as shown by the high mortality rates in all but the low-dose groups and by the lower mean body weights in dosed rats and mice at all doses throughout most of the bioassay.
Because of this high number of deaths, time-adjusted statistics are used for the analyses of all incidences of tumors.
In male rats, the dose-related trend in the mid-and high-dose groups for the incidence of osteosarcoma at all sites was significant (P=0.002) using the respective vehicle-control group (vehicle controls 0/8, mid-dose 13/30, high-dose 12/18). Comparisons of the individual groups with respective control groups were also significant for the mid-dose (P=0.022) and high-dose (P=0.002) groups, but not for the low-dose group. In female rats, osteosarcoma was observed only in 1/8 high-dose animals.
Sarcomas and other related tumors of the peritoneum were observed in all three dosed groups of both male and female rats, but in none of the control groups (males: low-dose 5/30, mid-dose 3/26, high-dose 7/16; females: low-dose 1/35, mid-dose 5/30, high-dose 13/28). In both sexes, the dose-related trends were significant (males, P=0.006; females, P=0.002), and the comparison of the incidences in the high-dose females with the vehicle-control group was significant (P=0.016). None of the incidences in the individual dosed groups of males were significant when compared with vehicle controls. However, since the tumors were observed in all dosed groups but did not occur in historical-control animals at this laboratory, they are considered to be related to the administration of the chemical.
In female rats, the incidence of all tumors of epithelial origin of the mammary gland was significant only at the low dose (low-dose vehicle controls 1/10, low-dose 22/35, P=0.004). Adenocarcinomas of the mammary gland were observed in seven low-dose, five mid-dose, and two high-dose female rats, but in no control females. The reverse dose relationship of both benign and malignant tumors was probably due to the higher number of early deaths which occurred in the high-dose group.
In mice, the low survival in all dosed groups except the low-dose animals precluded an evaluation of the significance of the incidences of tumors. Lymphomas occurred in low-dose groups of both males and females; however, the incidence of lymphoma in different control groups was highly variable. The high incidence in the low-dose vehicle controls may have been due to a procedural problem associated with the possibility of transfer of tumor cells or oncogenic viruses during the intraperitoneal injection of the test chemical.
It is concluded that under the conditions of this bioassay, the low survival of the dosed and control mice and the possible procedural problems associated with the intraperitoneal injection of the chemical did not allow a determination to be made of the carcinogenicity of acronycine in this species. In Sprague-Dawley rats, acronycine in the vehicle of 0.05% polysorbate 80 in phosphate-buffered saline was carcinogenic, producing tumors of the mammary gland in females, osteosarcomas in males, and sarcomas and other related tumors of the peritoneum in both males and females.
Report Date: 1978