Sensitivity to carcinogenesis in nude mice: skin tumors caused by transplacental exposure to ethylnitrosourea.

Female athymic nude mice and their phenotypically normal littermates were exposed transplacentally to ethylnitrosourea. Skin tumors (papillomas and sebaceous adenomas) developed on the nude mice with an almost tenfold greater incidence than on their haired littermates. Skin tumors were also induced on nude mice but not haired controls by direct intraperitoneal treatment with ethylnitrosourea. These results indicate that nude mice have higher than normal susceptibility to carcinogenesis under some circumstances.

Lung tumorigenesis in mice after chronic exposure in early life to a low dose of dimethylnitrosamine.

Strain A female mice were exposed to 10 ppb dimethylnitrosamine (DMN) in their drinking water for 4 weeks before mating. Treatment was continued through pregnancy and lactation and after weaning until the progeny were 22 weeks old. The incidence of primary lung tumors among the treated progeny (23%) was significantly higher (P less than 0.021) than that among controls (8%). The effect of the DMN was greatest among the males: 32% had lung tumors, compared with 4% of the control males (P less than 0.016). The DMN-exposed females also had a higher lung tumor incidence than did the controls, but the difference was not of statistical significance. These results demonstrate carcinogenicity of DMN at a dose approaching amounts possibly encountered by the human population as a result of environmental exposure.

Effects of polychlorinated biphenyls on lung and liver tumors initiated in suckling mice by N-nitrosodimethylamine.

A mixture of polychlorinated biphenyls (PCB), Aroclor 1254, was administered ip (500 mg/kg) to pregnant Swiss noninbred CD-1 mice on the 19th day of gestation. The suckling offspring of these mice and of controls were then treated ip with 5 mg N-nitrosodimethylamine (DMN)/kg on postnatal day 4 or day 14. The progeny were killed at 28 weeks or 18 months of age. The DMN treatment caused lung and liver tumors. Among the mice given DMN on day 14, exposure also to PCB resulted in a lower tumor incidence in some of the treatment groups. This protective action was most evident for lung tumors in both sexes at 18 months of age and for liver tumors in males at 28 weeks. However, the PCB exposure also led to significant increases in the percentage of mice with extensive DMN-initiated liver tumors at 18 months of age compared to the results obtained when only DMN was given. This effect was most pronounced in mice given DMN on postnatal day 4.

Increased incidence of mammary tumors in rats after direct or transplacental exposure to 3-hydroxyxanthine.

Rats were exposed directly or transplacentally to the carcinogenic purine N-oxide 3-hydroxyxanthine (3-OH-X). Among female noninbred Wistar rats given 3-OH-X sc, beginning at suckling or weaning ages, there was a significantly greater proportion of mammary tumor bearers and a higher mean number of mammary tumors per rat than among controls. This effect was seen even at low doses producing no other neoplasms such as hepatic carcinomas or fibrosarcomas and fibromas at the site of injection. Noninbred Sprague-Dawley rats, treated transplacentally with 3-OH-X by ip injection into pregnant females, also also had a significantly greater incidence of mammary tumors than did controls.

3-Hydroxyxanthine: transplacental effects and ontogeny of related sulfate metabolism in rats and mice.

The ontogeny of sulfate metabolism related to the metabolic activation of the carcinogenic purine N-oxide 3-hydroxyxanthine (3-OH-X) was studied in noninbred Sprague-Dawley rats. Sulfotransferase activity toward 3-OH-X was detectable in most fetal livers near term at about 25% of adult values and increased slowly after birth. This activity was also present in placentas. Compared to 3-OH-X sulfotransferase, sulfotransferase activity toward p-nitrophenol was lower in fetal livers and was not detected in placentas. Sulfohydrolase activity toward 3'-phosphoadenosine-5'-phosphosulfate was higher in fetal and newborn livers and in placentas than in adult liver. In a parallel transplacential carcinogenicity assay, a low but significant percentage of male rats exposed as fetuses to multiple high doses of 3-OH-X developed single liver carcinomas. After the lowest transplacental dose, the incidence of degenerative kidney disease in old male offspring was significantly higher than that in controls. In an assay with mice, (C57BL/6 X BALB/c)F1 mice exposed transplacentally to 3-OH-X experienced significantly greater perinatal morality and fewer lung adenomas among the surviviors at 20 months of age than did the controls.

Transplacental lung tumorigenesis in the athymic mouse.

Female BALB/c nu/+ mice, pregnant by nu/+ males (nu: gene for hairlessness-athymia) were given injections of urethan, a transplacental tumorigen, on Day 17 or 19 of gestation. After an average of 16 weeks under clean conventional conditions, the incidence of primary lung tumors was similar in nude and normal offspring treated with carcinogen on either gestational day, with a higher incidence after treatment of Day 19. Thus, the absence of thymus did not affect the occurrence of transplacentally induced primary lung tumors or alter the well-known perinatal increase in sensitivity. Histologically, the nu/nu tumors differed from normal in the appearance of many atypical basophilic cells and in a tendency to invade both the parenchyma and the pleural surface. These results suggested progression of the lung adenomas to a more atypical, invasive form, a progression that may have occurred prematurely in the absence of thymus-dependent immune response.

Effects of cimetidine, nitrite, cimetidine plus nitrite, and nitrosocimetidine on tumors in mice following transplacental plus chronic lifetime exposure.

Cimetidine (CM), a drug widely prescribed for ulcers, readily undergoes nitrosation to form nitrosocimetidine (NCM), a genotoxic agent. In a test of the chronic effects of NCM in mice, (C57BL/6 X BALB/c)F1 mice were exposed chronically to NCM (113 or 1130 ppm) in the drinking water from preconception through prenatal and neonatal development and adult life. Each group consisted of 40 to 80 mice of each sex, and median survival time was 27 months. Other groups were given CM alone or in combination with NaNO2 (184 or 1840 ppm), or NaNO2 alone. None of the chemical treatments had large effects on reproductive parameters, survival, or incidence of nonneoplastic lesions. CM treatment was associated with a small but significant increase in incidence of lymphomas in females, 41 of 59 (69%), compared with 31 of 66 controls (47%, P = 0.01). No females receiving either dose of NCM developed mammary carcinomas (0 of 91), compared with an incidence of four of 66 controls (6%, P = 0.03). Males given the high-dose combination of CM and NaNO2 showed a higher incidence of lung tumor bearers than controls (71 of 79 versus 30 of 52, P less than 0.01) and also experienced a significant, dose-dependent increase in numbers of large lung tumors (greater than 1 cm in diameter), lung carcinoma, and metastatic lung tumors. Females given the higher dose of NCM had significantly greater incidence of mice with large lung tumors than controls (nine of 41 versus three of 66, P = 0.009). The possibility of carcinogenicity of cimetidine, nitrosocimetidine, and cimetidine plus nitrite is discussed.

Oncogenicity of purine 3-oxide and unsubstituted purine in rats.

Injection s.c. of purine 3-oxide into Wistar rats resulted in the appearance of sarcomas and fibromas at the interscapular site of administration, carcinomas in the liver, and a high incidence of s.c. fibromas in the hip at a distance from the site of injection. A small number of liver tumors but not tumors at the injection site appeared in rats to which the parent compound, purine, was administered. Oxidation of purine 3-oxide by xanthine oxidase was found to occur in two steps to yield the potent oncogen 3-hydroxyxanthine. A similar process may occur in vivo since a protein preparation from rat s.c. tissue has similar oxidizing activity.

Therapy of 7,12-dimethylbenz(a)anthracene-induced rat mammary carcinomas with combinations of 5-fluorouracil and 2 alpha-methyldihydrotestosterone propionate.

This investigation was undertaken to determine whether a combination of a cytotoxic drug with a sex hormone would provide efficacious therapy for mammary carcinomas. Established, 7,12-dimethylbenz(a)anthracene-induced rat mammary carcinomas were treated with 5-fluorouracil (5-FUra) and 2 alpha-methyldihydrotestosterone propionate (MDTP) for 4 weeks. At end of therapy, pooled data showed 21% of the tumors in complete remission (CR) in rats given 5-FUra at 17.5 mg/kg/day and 3% in those given 8 mg/kg/day. Administration of MDTP at 1.25 to 5 mg/kg/day yielded 15 to 48% tumor CR. The combination of 5-FUra at 17.5 mg/kg/day with MDTP at 5, 2.5, and 1.25 mg/kg/day induced, respectively, 96, 91, and 75% CR. Maxima of 100, 100, and 92% CR were obtained in single tests at these respective doses. Therapy with combinations of 5-FUra at 8 mg/day and MDTP at 2.5 and 1.25 mg/kg/day yielded, respectively, 69 and 61% tumor CR. Appearance of new tumors during and after therapy was controlled more effectively by combinations of the two agents. Analysis of percentage of tumor CR showed marked synergism for 5-FUra and MDTP. A second course of combination therapy effectively prolonged duration of CR. Therapy with the cytotoxic drug 5-FUra in combination with the androgen analog MDTP is highly efficacious against induced mammary carcinomas.

Comparative effects of a series of prolactin inhibitors, 17beta-estradiol and 2alpha-methyldihydrotestosterone propionate, on growth of 7,12-dimethylbenz(a)anthracene-induced rat mammary carcinomas.

Eight ergot alkaloids and ergoline derivatives, effective prolactin inhibitors, were tested for activity against DMBA-induced rat mammary carcinomas. Compounds were administered daily, 5 times/week for 4 weeks, and rats were observed for an additional 4 weeks. Groups treated with androgen and estrogen were used as positive controls. Those ergot compounds and ergolines that proved to be highly effective in reducing tumor size or in inducing regression of tumors to nonpalpability were Deprenon (D-6-methyl-8-ergolin-I-ylacetic acid amide) and ergocryptine; effective to an intermediate degree were Dironyl [N-(D-6-methyl-8-isoergolin-I-yl)-N',N'-diethylurea], ergocornine, and Lysenyl [N-(D-6-methyl-8-isoergolenyl)-N',N'-diethyl-urea]; and effective to a minimal degree were Lergotrile (2-chloro-6-methylergoline-8beta-acetonitrile), CB-154, and 6605-VUFB (D-6-methyl-8-cyanomethylergolin-I). Remission of many individual carcinomas was brief, and duration of complete regression (all tumors in the rat were nonpalpable) was less than 10 weeks.

Qualitative histological differences between transplacentally-induced lung tumors in young and aging mice.

Transplacentally-induced lung tumors arising in BALB/c mice 38-45 weeks old (late crop) were significantly larger and more invasive of the surrounding lung parenchyma than were the tumors appearing at 10-36 weeks (early crop). The late-crop tumors were also somewhat more papillary and heterogeneous. Development of the 2 crops of tumors from different cell types of origin is postulated. A specific association of lymphocytes with the pleural surfaces of some tumors was noted and this association was significantly more likely for tumors invading the parenchyma than for non-invasive ones.

N6(Methylnitroso)adenosine: a carcinogenic nitrosamine derived from a naturally-occurring nucleoside.

N6(Methylnitroso) adenosine (M6(NO)Ado) is found readily under acidic conditions by the interaction of nitrite with 6-methyladenosine, a naturally-occurring nucleoside. Swiss mice were treated with M6(NO)Ado by injection (40 mg/kg each treatment) transplacentally and then as newborns and young adults. The incidences of lymphomas, primary lung tumors, and hepatic neoplasms were significantly greater in these treated animals than in controls. These results demonstrate the tumorigenicity of M6(NO)Ado.

Carcinogenic effects of intracolonic benzo[a]pyrene in beta-naphthoflavone-induced mice.

Benzo[a]pyrene (BP) was administered intracolonically to ICR/Ha and C57Bl/6 female mice, 1 mg/mouse, once weekly for 14 weeks. Half of the mice received beta-naphthoflavone (beta-NF, a mixed-function oxygenase inducer) i.p. 24 h prior to the BP. No colonic neoplasms were found in any of the mice after 18 months. However, the BP treatment did cause a significant increase in numbers of primary lung tumors, forestomach papillomas, mammary carcinomas, and sarcomas in one or both strains, relative to controls, and the incidence of all of these except for the sarcomas was significantly reduced by treatment with beta-NF prior to BP. Overall, the beta-NF pretreatment reduced total incidence of neoplasms by about 30% in the ICR/Ha mice and by about 60% in the C57Bl/6 mice, and did not potentiate the action of the carcinogen in any organ.

Silent, chronic, massive pulmonary thromboembolism masquerading as bronchogenic carcinoma.

A unique case is described of a 64-year-old white woman who had silent thromboembolic occlusion of the right pulmonary artery. Over the ensuing months, severe pulmonary hypertension developed, as manifested by marked dilatation and atherosclerosis of the right and left pulmonary arteries and severe right ventricular hypertrophy. Nevertheless, she remained fully ambulatory and felt generally well throughout this time. Eventually, however, the pulmonary arteries became so dilated that they compressed the recurrent laryngeal nerve as it looped under the aortic arch, and it was the resulting hoarseness that first caused the patient to seek medical attention. A work-up disclosed normal peripheral lung fields on x-ray study and a large dense right hilar mass. Accordingly, the patient was subjected to an exploratory thoracotomy on the reasonable but mistaken diagnosis of bronchogenic carcinoma. After the following operation, her condition deteriorated. She developed bronchopneumonia which, when superimposed on her already precariously reduced cardiopulmonary function, precipitated respiratory insufficiency. An independent stroke was the immediate cause of death.

Nursing care protocols for the kidney/islet cell transplant recipient.

Statistically 3 out of 4 patients with diabetes mellitus die from the secondary effects of the disease. Approximately 30%-40% of patients with end stage renal disease (ESRD) have diabetes. Simultaneous kidney/islet cell transplantation offers an innovative approach to the treatment of these chronic and disabling illnesses. Nursing care priorities are directed at maintaining central venous access and normoglycemia. Prescribed nursing care protocols require specialized postoperative assessments, interventions, and intensive patient education. These protocols have been developed in order to foster islet cell graft revascularization and ultimately to eliminate exogenous insulin requirements and regression of secondary complications of diabetes.

Induction of reproductive system tumors in mice by N6-(methylnitroso)-adenosine and a tumorigenic effect of its combined precursors.

Interaction of the naturally-occurring nucleoside, N6-methyl adenosine, with nitrite, a reaction that occurs readily under acidic conditions, results in the formation of a nitrosamine, N6-(methylnitroso) adenosine[m6(NO)Ado]. This nitrosamine was given in the drinking water (1 mM solution) of non-inbred Swiss mice from 3 weeks of age until death. It caused a significant increase in the incidence of primary lung tumors, compared with controls. It also induced reproductive tract tumors in 80% of the exposed females, including mammary tumors in 60% and uterine tumors in 25%. The precursors of m6(NO) Ado, m6Ado and nitrite, did not elevate tumor incidence when given singly, but when administered together resulted in a significant increase in numbers of lung tumors in the males. The nitrosamine base, N6-(methylnitroso)adenine, was found to be a less potent carcinogen than m6(NO)Ado, causing lung tumors only in males and possibly a few mammary tumors in females. These results indicate the in vivo formation of a carcinogen from m6Ado and nitrite, and show that m6(NO)Ado induces neoplasms in the reproductive system of mice, an unusual target for a N-nitroso carcinogen.