Tumor response in strain A mice exposed to silylating compounds used for gas-liquid chromatography.

Six reagents used to silylate, alkylate, or acylate compounds for ease of identification on gas chromatographic columns significantly increased the frequency of lung tumors in A/He mice.

Pulmonary adenoma response of strain A mice to sulfonic acid derivatives of 1- and 2-naphthylamines.

Various sulfonic acid derivatives of 1-naphthylamine and 2-naphthylamine were tested in inbred A/St (male and female) mice by the pulmonary adenoma bioassay to determine if this class of compounds, used as intermediates in the dye-stuff industry, possesses tumorigenic activity. Neither 1-naphthylamine nor the four sulfonic acid derivatives of 1-naphthylamine tested were tumorigenic. However, 2-naphthylamine and two of the three sulfonic acid derivatives of 2-naphthylamine tested produced statistically significant lung tumor responses at comparable doses. These results indicated that this class of compounds should be examined more extensively for carcinogenic activity.

Carcinogenic effects of intragastric 3-methylcholanthrene and 7,12-dimethylbenz[a]anthracene in Wistar and Sprague-Dawley rats.

In 2 experiments involving 384 rats of the Wistar (W) and Sprague-Dawley (SD) strains, the carcinogenic effects of repeated intragastric instillations of 3-methylcholanthrene (MCA) were compared with those of single intragastric doses of 7,12-dimethylbenz[a]anthracene (DMBA). Mammary carcinomas appeared in a higher proportion and earlier in SD than in W rats exposed to either carcinogen (during 36 weeks, 90 vs. 50% with MCA in SD and W rats, at an average of 12 and 15 weeks, respectively, and 80 vs. 64% with DMBA in SD and W rats, at an average of 16 and 22 weeks, respectively). Fibroadenomas of the breast were seen in 20 percent of SD rats by 36 weeks. In W rats observed for 1 year following DMBA administration, Fibroadenomas occurred in 64 percent and adenosis in 49 percent, at an average of 45 to 51 weeks, whereas after MCA administration these reactions occurred in less than 10 percent. Intraluminal secretion indicative of lactation was noted in approximately 20 percent of fibroadenomas and adenoses. Nine W rats developed lymphoma, 5 following DMBA and 4 following MCA administration. Uterine papillary formations were observed in 1 W and 2 SD rats, and uterine carcinomas in 2 SD rats; 3 animals had received DMBA and 2, MCA.

Strain A mouse pulmonary tumor test results for chemicals previously tested in the National Cancer Institute carcinogenicity tests.

Sixty-five chemicals were coded and examined for their ability to induce lung tumors in strain A/St (laboratory A) or strain A/J (laboratory B) mice. Thirty-five chemicals were tested in laboratory A only, 6 in laboratory B only, and 24 in both laboratories. Two-year carcinogenicity test results as well as genotoxicity test data are available for most of these chemicals. There was poor interlaboratory agreement in strain A test results for the 24 chemicals tested in both laboratories. In addition, there was poor agreement between strain A test results from either laboratory and 2-year carcinogenicity test results or genotoxicity results. Possible explanations for these findings include selection of a large number of aromatic amines in the group of chemicals submitted for strain A testing, differences in strain A testing protocols and in statistical analysis of results from the two laboratories, low sensitivity of the strain A/St mice used in this particular study, and general problems inherent in comparing any relatively short-term animal tumor model with 2-year carcinogenicity tests. Since there is no absolute reference for carcinogenicity, no one test system is better than another. Carcinogenicity test data are relevant only to the test model employed.

Committee on Growth, 1945-1956: another noble experiment.

The events of the creation, activities, and termination of the Committee on Growth of the National Research Council as the advisory body on research to the American Cancer Society, 1945 to 1956, are historical and instructive. It remains to be demonstrated that programmed research support is more effective than the less structured approaches represented by the Committee on Growth.

Inhibiting effect of caffeine on spontaneous and urethan-induced lung tumors in strain A mice.

The i.p. injection of caffeine (8, 20, and 40 mg/kg) 3 times weekly for 8 weeks suppressed the development of spontaneous pulmonary adenomas in strain A mice. The same caffeine injection scheme suppressed urethan (0.25 and 1.0 mg/g)-induced lung tumor development when caffeine treatment started 1 week before urethan administration, but this suppression was not significant when caffeine treatment was initiated 1 week after urethan injection. The most pronounced suppression of lung tumor formation occurred when caffeine was given as only two injections 3 hr before and 3 hr after urethan administration. The incorporation of [3H]thymidine into lung tissue DNA of caffeine-treated mice was impaired at the time of urethan administration. Also, caffeine partially antagonized the effects of urethan on lung tissue, as measured by [3H]thymidine incorporation studies. One interpretation of these results is that caffeine-induced suppression of DNA synthesis interferes with pulmonary adenoma induction by decreasing the affinity of lung tissue DNA for urethan. The finding that chronic caffeine treatment produced continued suppression of [3H]thymidine incorporation into lung tissue DNA suggests that caffeine-induced inhibition of spontaneous pulmonary adenoma formation is due to a general suppression of lung DNA-synthetic activity.

Murine pulmonary adenoma bioassay of potentially effective agents against slow-growing solid tumors.

An in vitro-in vivo system for screening potentially effective drugs against solid tumors is described. Drug toxicity to plateau-phase pulmonary adenoma cells is used as an in vitro screen for potential activity against solid tumors, since both plateau phase cultured cell populations and solid tumors are composed predominantly of nondividing cells. The effect of drugs with in vitro activity on the rate of appearance of urethan-induced adenomas on the lung surface of strain A mice in vivo is used to assess drug efficacy in the treatment of solid tumors, taking into consideration drug toxicity to and drug metabolism by the host. Arabinosylcytosine and hydroxyurea were ineffective against plateau phase cells in vitro, even at high concentrations (5 to 10 mg/ml), and did not affect pulmonary adenoma growth in vivo, even at toxic doses (arabinosylcytosine, 80 mg/kg; hydroxyurea, 800 mg/kg), as would be expected with these cell cycle-active drugs. Adriamycin, an effective agent against human solid tumors, was cytotoxic to plateau phase cultured cells (0% survivors at 1 mug/ml), and a dose of 2 mg/kg completely inhibited pulmonary adenoma growth in mice. Thus, this pulmonary adenoma bioassay would appear to effectively select for drugs which may be active against solid tumors in humans.

Bioassay of alkyl halides and nucleotide base analogs by pulmonary tumor response in strain A mice.

The production of lung adenomas in strain A mice following multiple injections of 17 alkyl halides and of 3 base analogs was investigated. A slight but significant increase in the average number of lung tumors per mouse was noted following the administration of methyl iodide, n- and i-propyl iodide, sec- and tert-butyl chloride, i-, sec-, and tert-butyl bromide, and n- and sec-butyl iodide. The administration of comparable doses of ethyl bromide, ethyl iodide, n-butyl chloride, benzyl chloride, and 1-chloromethylnaphthalene to mice resulted in no significant increase in the frequency of lung tumors over that seen in vehicle-treated control mice. n-Butyl bromide and tert-butyl iodide similarly appeared to have no significant effect on the lung tumor frequency, but these compounds were too toxic to be tested at the high dosages used with the other alkyl halides. 5-Iodo-, 5-bromo-, and 5-fluorodeoxyuridine also appeared to have no significant effect on the lung tumor frequency. These results indicate that a high proportion of low-molecular-weight alkyl halides may be weakly carcinogenic and provide evidence supporting an electrophilic hypothesis of carcinogenesis.

Increase in testis luteinizing hormone receptor by estrogen in mice susceptible to Leydig cell tumors.

In an investigation comparing two strains of mice (BALB/c, susceptible to estrogen-induced Leydig cell tumors and C3H, resistant to such tumors), we found that the Leydig cell-luteinizing hormone (LH) receptors increase in BALB/c mice and decrease in C3H mice during estrogen treatment. In the BALB/c strain, LH receptor content in the tested of mice treated 1, 2, 4, 6, or 8 weeks with diethylstilbestrol (DES) was 2.4- to 5.4-fold greater than that in the testes of untreated littermates. By 24 weeks of treatment, the receptor number had increased 10-fold. Likewise, two weeks of estradiol benzoate treatment in BALB/c mice resulted in a dose-dependent increase in LH receptor content. In contrast, in C3H mice, DES treatment resulted in a transient initial increase (60%), followed by a time-dependent decrease in testicular LH receptor number: 38 and 17% that of normal by six and eight weeks of treatment, respectively. In both strains of mice, DES-induced changes in 125I-labeled human chorionic gonadotropin binding reflected changes in LH receptor number rather than in receptor affinity (approximately 3 x 10(-11) M). The testis weights of BALB/c mice remained normal during DES treatment, whereas those of the C3H decreased with time. Sprague-Dawley rats, resistant to estrogen-induced Leydig cell tumors, like C3H mice, also underwent testicular atrophy and lost LH receptors during DES treatment. The present study demonstrates that estrogen treatment indices diametrically oppossed change in testicular LH receptor number in the two strains of mice with different susceptibilities to Leydig cell tumorigenesis.

Effect of commercial saccharin preparations on urethan-induced lung tumorigenesis in strain A mice.

The effect of commercial saccharin preparations on urethan-induced mouse lung tumorigenesis was assessed by gavaging groups of male strain A mice with 1-g/kg doses of each saccharin preparation on a daily basis 5 days/week. Gavage was initiated 1 week before i.p. injection of either a low (0.1 mg/g) or a high (1 mg/g) dose of urethan and continued until the mice were sacrificed 16 weeks after urethan administration. The average number of surface lung tumors per mouse for each group of mice was determined and was compared statistically with the appropriate control group. The commercial saccharin preparations did not produce an elevated lung tumor response when administered alone. One of the four saccharin preparations enhanced the lung tumor response to urethan when given in conjunction with the low dose of urethan, but this enhancement was not statistically significant. At the high urethan dose, all saccharin preparations produced a statistically significant enhancement of the lung tumor response to urethan.

Test for carcinogenicity of organic contaminants of United States drinking waters by pulmonary tumor response in strain A mice.

The production of lung adenomas in strain A following multiple i.p. injections of selected organic water contaminants was investigated. Of the 16 contaminants tested, only bromoform produced a pulmonary adenoma response that was significantly greater than the pulmonary adenoma response of vehicle-treated control mice.

Funding: grants or contracts? A survey of cancer scientists.

The members of the American Association for Cancer Research (AACR) were polled for their reactions to the current controversy of funding by research grant versus that by the research contract and to the nature of the scientific review appropriate for the evaluation of both types of applications. About 50% of the members responded; 97% of these felt that additional basic knowledge was absolutely essential or probably essential for the successful pursuit of the goals of the National Cancer Program. Eighty % of the respondents concluded that the funding of such research programs should be derived largely from grants rather than contracts. Most of the participants agreed that there should be a major rather than a minor redistribution of funds toward grants and away from contracts. About 50% of the respondent AACR members currently are being supported by research grants, about 10% receive contracts only, and another 25% of the members have both types of funds at their disposal. The group of contract-supported scientists felt less critical of contracts, but about one-half of that group also wished to see more funds going into the grant rather than into the contract programs for the additional support of basic research. There was considerable agreement among all groups of respondents that the review process for contracts should make much more active use of extramural peer evaluation to eliminate scientific inequities now existing between the two instruments for funding of work in cancer research.

Inhibition by magnesium and calcium acetates of lead subacetate- and nickel acetate-induced lung tumors in strain A mice.

The ability of the physiologically essential divalent metals calcium and magnesium to inhibit the tumorigenic activities of lead and nickel towards the lungs of strain A mice was investigated. The tumorigenic salts lead(II) subacetate and nickel(II) acetate were injected i.p. at their maximal tolerated doses (0.04 mmol/kg/injection of each metal) for a total of 24 injections, whenever possible. Calcium(II) acetate and magnesium(II) acetate were administered in the same preparation along with the lead and nickel salts at molar doses of approximately 1, 3, 10, and 30 times the maximal tolerated dose of the tumorigen. The animals were sacrificed 30 weeks after the first injection, and the lung tumors were counted. The lead and nickel salts, administered alone, each produced a significant increase in the observed number of lung adenomas per mouse. When administered with any of the doses of calcium acetate or magnesium acetate tested, neither lead subacetate nor nickel acetate showed any significant tumorigenic activity. Calcium acetate alone (total dose, 11 mmol/kg of body weight) appeared to yield a significant rise in lung adenomas observed. The results indicate an antagonism between magnesium and calcium and the tumorigenic metals nickel and lead.

Test for carcinogenicity of metallic compounds by the pulmonary tumor response in strain A mice.

The production of lung adenomas in strain A mice following multiple i.p. injections of 13 metallic compounds was investigated. A significant increase in the average number of lung tumors per mouse was noted following the administration of lead subacetate, manganous sulfate, molybdenum trioxide, and nickelous acetate. These four compounds can be considered as weakly carcinogenic for lung tumors in strain A mice.

Effect of lactate dehydrogenase virus on chemically induced mouse lung tumorigenesis.

Lactate dehydrogenase virus is the third in a series of viruses which have been examined for the capacity to alter chemically induced mouse lung tumorigenesis. This virus was given to strain A mice by i.p. injection either 4 weeks before, on the same days as, 4 weeks after, or 8 weeks after the s.c. injection of urethan (either 0.25 or 1.0 mg/g). The pulmonary adenoma response to urethan was suppressed in all of the lactate dehydrogenase-infected mice, with a maximum suppression of 30 to 40% when the virus was given simultaneously with or 4 weeks after urethan. As with murine sarcoma virus and reovirus, it is postulated that this suppression of chemically induced mouse lung tumorigenesis is due to virally induced alterations in the immune response of the mouse to chemically induced tumors.

A comparison of mutagenic and carcinogenic activities of aniline mustards.

A set of 15 derivatives of aniline mustard (I) was tested to give a quantitative measure of mutagenicity in Salmonella typhimurium TA-1535 and TA-100 and also carcinogenicity as lung tumors in strain-A mice. The structural variation in the set was chosen to minimize collinearity between hydrophobic, electronic, and molar refractive properties. By these measures, there was not a direct relationship between mutagenicity and carcinogenicity; in fact, since the 4-OPh analogue ranked highest in mutagenicity and among the lowest in carcinogenicity, while the reverse was noted for the 3,5-(NHCONH2)2 analogue, an inverse relationship was marginally significant. S-9 activation was required in the Ames test using TA-100, and the dose-response curve, prior to toxicity, appeared biphasic.

Lung tumor response in mice to metals and metal salts.

Two studies tested the ability of metals and their salts to produce lung tumors in strain A mice. Of 13 compounds examined, lead subacetate, manganous sulfate, molybdenum trioxide, and nickelous acetate elicited a weakly carcinogenic response following intraperitoneal injection. Nine metallic compounds were negative. There was no evidence of cocarcinogenic effect between metals and the chemical carcinogen, 3-methylcholanthrene. On the basis of these and other data, recommendation is made for further investigations in metal carcinogenesis.