3,3'-Iminobis-1-propanol dimethanesulfonate (ester) hydrochloride, hereinafter called IPD, was synthesized from bis(3-hydroxypropyl)amine and methanesulfonic acid anhydride. It was found to have antitumor activity against a number of experimental tumors that were naturally resistant to nitrogen mustard and has been used in Japan for the treatment of myelogenous leukemia. IPD was selected for carcinogen bioassay as one agent in a series of anticancer drugs that are administered chronically in the treatment of human cancer.
A bioassay of IPD for possible carcinogenicity was conducted by administering the test chemical intraperitoneally to Sprague-Dawley rats and B6C3F1 mice.
The IPD was injected three times per week to groups of 35 animals, using doses of 12, 24, or 48 mg/kg for the rats, and 20 or 40 mg/kg for the mice. Rats at 12 mg/kg were treated for 52 weeks. Because of the toxicity of the chemical, administration of IPD for the group receiving 24 mg/kg was discontinued at week 34. Rats receiving 48 mg/kg were treated until all had died at week 23 (males) and week 27 (females). Both groups of mice were treated for 52 weeks. All survivors were killed after post-administration periods that varied among groups.
With rats, untreated and vehicle-control groups, each consisting of 10 males and 10 females, were started with the high- and mid-dose groups and additional untreated and vehicle-control groups of the same size were started with the low-dose groups. With mice, untreated and vehicle-control groups each consisted of 15 males and 15 females.
The toxicity of IPD was associated with lower mean body weights and lower rates of survival of both the rats and mice. The shortened life spans, particularly in the rats, reduced the likelihood of the development of tumors.
In rats, peritonitis and fibrous adhesions, possibly, from direct irritation by the test chemical were observed in most treated rats at necropsy. Sarcoma, fibroma, or fibrosarcomaof the peritoneum occurred in two low-dose male, one mid-dose male, and one mid-dose female rats, but not in any control animals. Because of this low incidence, and because irritation by the test chemical have been involved in the pathogenesis, these tumors may have been due to local effects of the chemical.
In mice, lymphomas were observed at the following incidences (males: controls 0/14, low-dose 0/26, high-dose 3/21; females: controls 1/15, low-dose 2/29, high-dose, 6/27). The Tarone test for life-table analysis of the probability of survival without lymphoma indicated a significant positive dose-related increase of lymphomas with a probability level of 0.011 for male mice and 0.003 for female mice.
Squamous-cell carcinoma was noted in the mice (low-dose males 6/26, high-dose females 2/27). Seven of these tumors were observed in subcutaneous tissue in the inguinal region near the sites of injection. Although not statistically significant, this tumor may be associated with administration of IPD.
Tumors of the peritoneum in rats and tumors in the subcutaneous tissue in mice may have been due to local effects related to administration of the test chemical. The lymphomas in mice, although marginally significant, were too few in number to clearly be related to dosing.
Conclusions from this study are limited by early deaths and toxicity, but the appearance of tumors in the peritoneum near the injection sites in both rats and mice indicate the carcinogenic potential of IPD.