The effect of norethynodrelmestranol (“Enovid”) pretreatment on the metabolism of 7,12-dimethylbenz(a)anthracene (DMBA) was examined in vivo in rats and hamsters, and in vitro in hamsters. “Enovid” pretreatment caused a decrease in bile flow, and increased by 44% the amount of DMBA metabolites excreted in the bile of rats; however, such effects were not found in hamsters. In vitro metabolism of DMBA by hamster liver 10,000g homogenates was also not modified by “Enovid” pretreatment. Aroclor and 3-methylcholanthrene pretreatments were used as positive controls for induction. Aroclor induced in vitro DMBA metabolism in hamster liver homogenates, whereas 3-methylcholanthrene unexpectedly had no effect. Results for in vitro benzo(a)pyrene metabolism were similar to those for DMBA. These studies suggest that the reported enhancement by Enovid E pretreatment of DMBA mammary carcinogenesis in the hamster is not mediated by an effect on overall hepatic metabolic activation of DMBA.

Native carrageenan (Gelcarin), a widely used food additive, was tested for carcinogenicity in MRC rats and Syrian golden hamsters through lifespan studies. Three groups of 30 males and 30 females from these species received carrageenan at dose levels of either 5%, 2.5% or 0.5% in the diet daily for the animal's lifespan. A trend toward an increased incidence of benign mammary tumors in females and testicular neoplasms in males occurred at the median dose level (2.5%); however, the incidence of these tumors was not statistically significant. Hamsters did not develop neoplasms in response to treatment at any dose levels. From the results of this experiment, carrageenan demonstrated no carcinogenic effects in either species.

Metronidazole, a chemotherapeutic agent against trichomonas infection, was tested for carcinogenicity in noninbred Sas:MRC(WI)BR rats. Three groups were given the drug for life at dose levels of 0.6%, 0.3%, and 0.06% in a powdered diet. The incidence of mammary tumors (P less than 0.020) and hepatomas (P less than 0.050) increased significantly among females given the highest dose (0.6%). Also, the rates of Leydig cell tumors of the testes (P less than 0.040) and pituitary adenomas (P less than 0.040) were statistically significant among males given the highest dose (0.6%). Results are discussed in light of a possible hazard of this drug to humans.

Prenatal exposure to a single dose of diethylstilbestrol (DES) produced a significant increase in carcinogenic response of hamster progeny that were subsequently subjected to the carcinogenic stimulus of 7,12-dimethylbenz(a)anthracene (DMBA) during postnatal life. The compounds were administered according to the following schedules. The pregnant animals (second group) received a single dose of DES, 10 mg/kg, on Day 14 of gestation. Postnatally, at 6 weeks of age, the progeny were given DMBA, 25 mg/kg p.o., twice weekly for 8 weeks. The first group received DMBA at 6 weeks of age, 30 mg/kg p.o., twice weekly for 18 weeks. The progeny exposed to DES prenatally and DMBA postnatally (DES-DMBA-exposed progeny) developed a greater multiplicity of tumors per tumor-bearing animal (p less than 0.001) and higher rates of neoplasms of the reproductive tract, e.g., ovarian and uterine tumors, mammary gland and forestomach tumors, and dermal melanomas. The prenatally DES-exposed progeny also had significantly higher incidences of malignant tumors, e.g., carcinomas of the mammary gland (p less than 0.001) and carcinomas of the forestomach (p less than 0.001), than did the hamsters given DMBA alone during postnatal life. Endocrine imbalance produced by exposure in utero may heighten the sensitivity of the progeny to development of neoplasms after a challenge with carcinogenic stimuli in adult life. The significance of these experimental data to the human situation is discussed.

The relationship between volume increases of pulmonary metastases and their doubling time values was studied in patients with osteogenic sarcomas, soft tissue sarcomas, and malignant melanomas. From 60 patients (18 with osteogenic sarcomas, 24 with soft tissue sarcomas, and 18 with malignant melanomas), a total of 197 metastases were measured and 362 doubling time values were calculated. The overall median for doubling time was 32 days. The smaller metastases grew significantly faster (median, 26 days) when compared to the growth rate for the larger metastases (median, 47 days). The measured doubling time values seemed to vary similarly among them, since analysis of the growth rate for small metastases from all three types of cancers showed essentially similar values for the median doubling time. The recorded respective median values for doubling time of pulmonary metastases were 26 days for osteogenic sarcomas, 26 days for soft tissue sarcomas, and 24 days for malignant melanomas. A similar tendency was observed for larger metastases, in which somewhat larger differences were found when respective values for the median were compared. Subsequently, the time interval between initial diagnosis and the onset of pulmonary metastases and the time lapse from the appearance of metastases to patient9s death were calculated and compared for all three instances studied. The comparison of time intervals from initial diagnosis to the onset of metastases obtained in all three instances revealed differences of duration, but the time interval passing from the appearance of metastases to patient9s death appeared similar for all three types of cancers studied. The presented data indicate that similar growth control mechanisms operated in the pulmonary metastatic growth processes in all three instances reported.

Data are presented from studies on Syrian golden hamsters with the ENU precursors, EU, and NaNO2, given transplacentally and in adulthood, and with transplacentally administered DES. Hormone modification by gonadectomy of offspring prenatally exposed to ENU caused a significantly greater incidence and multiplicity of PNS neoplasms and other tumor types in orchidectomized males, compared with intact males, and in ovariectomized and intact females. That PNS tumors in gonadectomized males appeared within a significantly shorter latency period indicated that endogenously generated androgens inhibited neoplastic development. The endocrine imbalance also induced a higher incidence of neoplasia in other tissues and organs, e.g., skin melanomas, thyroid and adrenal cortex tumors, and notably gliomas in the CNS of ovariectomized female siblings. Exposure to single doses of ENU on days 12, 13, 14, and/or 15 caused PNS tumors predominantly in females and with an increased frequency in progeny treated during the final days of gestation. The spectrum of neoplasms was greater and their incidence significant in ENU-treated adult hamsters; the tumor types different from those of transplacentally treated animals (i.e., vascular, vaginal, and ovarian tumors and fore-stomach papillomas were seen). Determining factors in carcinogenesis at the time of carcinogen treatment possibly included stage of ontogenic development, degree of cell differentiation, hormone state of host, age, total dose, and duration of treatment. DES results indicated that the haster may be a useful model for reproducing lesions similar to those observed in children of mothers treated with this drug during pregnancy.

Griseofulvin, an antibiotic used to treat dermatophystosis, was tested for carcinogenicity in mice, rats and hamsters. Three groups of mice and rats were given the drug in powdered diet in alternating 5-week periods for life, at dose levels of 3.0%, 1.5% and 0.3% (mice) and 2.0%, 1.0% and 0.2% (rats). A group of mice and 3 groups of hamsters received continuous daily treatment for life with griseofulvin at 3.0%, 1.5%, 0.3% and 0.1% dose levels respectively. A significant incidence of hepatic tumours was observed at the 2 higher treatment levels in mice. Also, statistically significant rates (P less than or equal to 0.001 and/or P less than or equal to 0.020) of thyroid tumours, indicating a dose-response, were recorded in male rats at the 2.0%, 1.0%, and 0.2% dose levels, and in females at the 2.0% and 1.0% dose levels. Hamsters did not develop neoplasms in response to treatment at any level.

The effects of gonadectomy on tumors induced transplancentally by the ethylnitrosourea precursors, ethylurea and sodium nitrite, were investigated in hamsters. The pregnant hamsters were exposed to four daily doses of ethylurea (100 mg/kg) and sodium nitrite (50 mg/kg) administered from Day 12 to 15 of pregnancy. Weaned offspring were gonadectomized when they reached the age of 5 weeks. Orchiectomized male progeny showed a multiplicity and greater frequency of peripheral nervous system tumors and of any other tumor types than did intact males or their ovariectomized and intact female siblings. The possible inhibitory effects of endogenous androgens on the development and growth of neurogenic tumors in the peripheral nervous system and the influence of an induced endocrinal imbalance on prenatally induced neoplasms are discussed.

Summary The simultaneous p.o. administration of ethylnitrosourea precursors ethylurea and sodium nitrite (NaNO2) to adult hamsters at daily dosages of 100 and 50 mg/kg for a total of 40 dosages during the first 6 weeks of the experiment resulted in the induction of multiple types of neoplasms. Eighty-five % of the treated animals developed an average of over three tumors per tumor-bearing animal. However, only 14% of the animals treated with ethylurea alone for the same duration at doses of 100 mg/kg had single tumors, while 16% of the untreated controls also developed single neoplasms. The incidence of vascular tumors in the spleen and liver, papillomas of the forestomach and vagina, ovarian tumors, and neurogenic tumors in the peripheral nervous system was significant. However, lower frequencies were noted for some neoplasms that rarely occur in this species. The findings demonstrated that, under present experimental conditions, adult hamsters develop a broader spectrum of neoplasms than do prenatally exposed animals to identical precursors. The functional and developmental state of the organ at the time of exposure to carcinogenic stimuli and certain other factors were considered possible determinants influencing the development of some tumors.

A description is given of three cases of ganglioneuromas, which originated from ganglia of the sympathetic chain of hamsters. Other reports of such tumors in this species are reviewed and the literature relative to hamster ganglioneuromas presented. In addition, the possible genesis of origin from adult ganglion cells upon the action of carcinogenic stimuli is discussed.

To assess their carcinogenic effects, the ethylnitrosourea (ENU) precursors, ethylurea and sodium nitrite, [were administered to pregnant hamsters as a single intragastic] dose on day 15 of gestation, or introduced into the cecum on day 14. Since sodium ascorbate (NaASC) inhibits the biosynthesis of nitrosamides, identical doses of the precursors were given concomitantly with NaASC. Progeny of mothers treater intragastrically developed significant incidences of neurogenic tumors of the peripheral nervous system, with a predominance in females. The concurrent administration of NaASC with ENU precursors prevented carcinogenic effects in the progency, whereas the simultaneous inoculation of the precursors into the cecum produced no carcinogenic effects in the offspring.

The effect of diethylstilbestrol (DES) was investigated in Syrian golden hamster progeny exposed during the terminal stages of gestation. Eleven pregnant hamsters were treated with 40 or 20 mg/kg body weight (b.w.) of DES. This treatment led to hyperplastic and neoplastic lesions in the reproductive system of most female progeny and was associated with continuous estrogenic stimulation. Seventy per cent of the male progeny developed spermatic granulomas of the epididymis and testis. The incidence and severity of these lesions were proportional to the dose of DES.