Induction Of Tumors In Mice Research Articles

Deletion of cellular DNA at site of viral DNA insertion in the adenovirus type 12-induced mouse tumor CBA-12-1-T.

The adenovirus type 12 (Ad12)-induced mouse tumor CBA-12-1-T contains greater than 30 copies of viral DNA integrated into cellular DNA. One of the sites of linkage between the left terminus of Ad12 DNA and mouse DNA was cloned, mapped and sequenced by using conventional techniques. The preinsertion sequence was also cloned from normal CBA/J mouse DNA and sequenced. The sequence data and blotting analyses demonstrated that at the site of linkage nine nucleotide pairs of viral DNA and at least 1500 to 1600 nucleotide pairs of cellular DNA were deleted. Up to the site of linkage, the cellular DNA sequence in CBA-12-1-T tumor DNA and the preinsertion sequence in CBA/J mouse cells were identical. The site of Ad12 DNA integration was found to be located close to a site of transition from unique to repetitive cellular DNA sequences. The nucleotide sequence at the site of linkage and at the preinsertion site revealed palindromic stretches of 5 and 10 nucleotides pairs, respectively. Scattered patch homologies (8-10 nucleotide pairs long) were observed between adenoviral and cellular DNAs. A hypothetical model for DNA arrangements at the site of recombination is presented.

Correlation between tumor-specific surface antigens and src gene expression in Rous sarcoma virus-induced rat tumors

Immunization with Rous sarcoma virus (RSV)-induced mouse tumors or with SR-3Y1 or NY8-3Y1 rat fibroblasts transformed by a wild type RSV or an env gene deletion mutant of RSV induced complete transplantation resistance against an RSV-induced mouse tumor (CSA1M) in syngeneic hosts. On the other hand, 10 of 19 mice immunized with ts68-3Y1 rat fibroblasts transformed by an src gene temperature-sensitive mutant of RSV (permissive temperature: 33–35° C) could not reject the CSA1M. SR-3Y1, NY8-3Y1 and RSV-induced mouse tumors expressed a common tumor-specific cell-surface antigen (TSSA) detected by a syngeneic rat antiserum against NY8-3Y1. In ts68-3Y1, expression of the TSSA was temperature-sensitive, TSSA being detected only when ts68-3Y1 was cultivated at the permissive temperature. Immunoprecipitation showed that serum from a rabbit bearing an RSV-induced tumor detected a 60- kdalton protein in cell extracts from SR-3Y1 and NY8-3Y1. Antiserum to NY8-3Y1 failed to detect this protein. These results suggest that the tumor-specific surface antigen(s) on RSV-induced mammalian tumors was coded for by an RSV src gene that was not identical with the simple form of the 60- kdalton protein identified.

The UKEMS genotoxicity trial a summary of the assays for skin tumour induction in mice, the subcutaneous implant test and the sebaceous gland suppression test

The UKEMS genotoxicity trial a summary of the assays for skin tumour induction in mice, the subcutaneous implant test and the sebaceous gland suppression test

Susceptibility of BALB/cGnDu mice to transplantable tumors, in vitro transformed cells, BK and SV40 viruses, and chemical carcinogens.

Various oncogenic agents were employed in tumor susceptibility studies of an inbred subline of BALB/cGn mice, BALB/cGnDu, which carries a mutant gene that results in spontaneous thymic involution in homozygous recessive individuals. Of 18 transplantable tumors, 3 in vitro transformed cell lines, 2 oncogenic papovaviruses and 3 chemical carcinogens evaluated, only the Harding-Passey amelanotic melanoma produced tumors in 100% of the normal adult mice injected. The S180 pleomorphic sarcoma produced tumors in 56% of normal adult mice. Although not tumorigenic in adults, the mKSA, Morris (rat) hepatoma No. 7777, and a human papovavirus - transformed human cell induced mouse tumor line [GI110(BK) B6D2 Tu] formed tumors in 100, 62 and 70%, respectively, of recipients inoculated as neonates. SV40 and human papovavirus BK virions, as well as sV40, BK, and spontaneous in vitro transformed BALB/cGnDu cells were not tumorigenic. Although the histocompatibility antigens of these animals have not been studied, no correlations could be made between the tumor susceptibility of these animals with regard to the commonly employed inbred line BALB/c nor with regard to the range of host susceptibility of the transplantable tumors. This inbred subline represents a new strain of mice whose genetic defect makes it useful for transplantation immunology and physiological genetics.

Effect of age on induction of intestinal tumors in mice by 1,2-dimethylhydrazine

1,2-Dimethylhydrazine was administered subcutaneously in a dose of 8 mg/kg bw to 2-, 8- and 12-month-old female CBA mice for 25 weeks. The animals were serially killed 26-35 weeks after the beginning of treatment. The incidence of colon tumors in 2-month-old mice was always significantly lower (P less than 0.001) than in 8- or 12-month-old mice. The incidence of tumors with invasive growth in 12-month-old mice was significantly higher (P less than 0.05) than in 8-month-old mice. Mathematical evaluation allowed the conclusion about the 1.8-fold shortening of the colon tumor latency period in old mice as compared to the young mice.

The influence of hyper- and hypothyroid states on the incidence of 3-methylcholanthrene-induced tumor in DDY mice.

In female DDY mice. the incidence of 3-methylcholanthreneinduced skin tumors was increased in the hypothyroid state produced by the administration of Endojodin or l-methyl-2-mercaptoimidazole (p < 0.0 I) and decreased in the hyperthyroid state produced by L-thyroxine administration (p < 0.05) compared with controls. The calorigenic effect or the direct action of thyroid hormones may correlate with tumor induction in mice.

Early changes of hematopoietic tissues in mice treated with intravenous pulse-doses of 7,12-dimethylbenz(a)anthracene.

Repeated intravenous injections of 7,12-dimethylbenz(a)anthracene (abbr. DMBA), four times weekly, induced several kinds of tumors in 26 mice (83.9%) out of 31 ddO mice, including 13 leukemias and 6 ovarian tumors. All leukemias were of lymphatic type, and 8 cases out of 13 leukemias were of thymus type. The thymus was involved by leukemic cells in 12 cases. All ovarian tumors were diagnosed as granulosa cell tumors histologically. During the treatment of DMBA, two types of changes in organs and blood were observed: one was a striking decrease of weight or organs or number of cells followed by prompt recovery as found in the spleen, red blood cells, and granulocytes in the peripheral blood; the other was moderate but long-standing decrease with little recovery as found in the thymus, ovaries, uterus, and lymphocytes in the peripheral blood. Unlike DMBA, the weight of the thymus was strikingly decreased by predonisolone, one of corticosteroids, whereas reactions of the spleen and the lymph nodes were not remarkable. Autoradiographical studies revealed a severe reduction followed by a marked rebound of labeling index in the red pulp of the spleen, but not in the white pulps of the spleen and cortex of the thymus. From these observations, it is concluded that a mild but long standing injury was noticed in the tissues which were the main sites of the tumorigenesis in mice by DMBA, and a severe but transient injury may not be related to induction of tumors in mice by DMBA.

Induction of malignant tumors in mice by methylcholanthrene bound covalently with bovine serum albumin

The carcinogenic properties of 3-methylcholanthrene, covalently (by means of bisdiazotized benzidine) bound to protein, were studied in experiments on mice. It was shown that binding with protein in this way does not abolish carcinogenic activity: Sarcomas developed rapidly at the sites of subcutaneous injection of the conjugate. For this reason, immunization of animals with conjugated 3-methyl-cholanthrene-protein antigen in order to obtain antibodies specifically binding the carcinogen is difficult.

Caffeine enhances skin tumor induction in MICE

Caffeine increased the incidence of malignant tumors in mouse skin from 26% to 49% when the skins treated by a single exposure to beta rays and 20 subsequent paintings with 4-nitroquinoline 1-oxide (4NQO) was further treated by additional painting with caffeine on alternate days of the 4NQO painting.

Characteristics and in vitro Growth Influencing Effects of the Spleen Cell Population in a Methylcholanthrene Induced Mouse Sarcoma System

Effects of immunization on the growth of the early passages of two methylcholanthrene induced mouse tumors, MC57 X and MC57 Y, were different. For tumor X, immunization resulted in complete protection, while tumor Y was enhanced. The enhancing effect was individual tumor specific.The spleens of tumor bearing animals were enlarged and the proportion of blasts, EAC- and EA-rosettes were increased. This was the case for the T cell enriched population also. In lesser extent, such findings were also obtained in the lymph nodes.The spleens of control and tumor bearer animals were tested for effect on the in vitro growth of tumor cells. From both sources non-adherent subpopulations enriched in C3 receptor bearing cells substantially reduced the number of tumor cells. Using the T cell fractions, only those derived from tumor bearer spleens were active.The in vitro effects on the growth of the two tumors were cross-reactive. T cells exhibiting growth inhibition in vitro were detectable 13 days after subcutaneous inoculation, when the tumor was already measurable, while earlier the T cells enhanced the growth.The outcome of the in vitro tests reflected only the tumorous status of the animal and did not relate to preimmunization.

Effect of protease inhibitors in mice treated with the hepatocarcinogen, hexachlorocyclohexane (alpha-isomer) and the bladder carcinogen, N-butyl-N-(4-hydroxybutyl)nitrosamine.

Studies were made on the effect of protease inhibitors (pepstatin, leupeptin, and antipain) on the induction of tumors in mice by the alpha-isomer of 1,2,3,4,5,6-hexachlorocyclohexane (alpha-BHC) and by N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN). Animals were given 0.05% alpha-BHC in the diet or 0.05% BBN in their drinking water and then fed on a powder diet supplemented with 0.1% protease inhibitors. The incidence of liver nodular hyperplasias was significantly higher in the group treated with alpha-BHC and leupeptin than in the group treated with alpha-BIC alone, but pepstatin and antipain did not affect induction of liver nodular hyperplasias by alpha-BHC. None of the three protease inhibitors influenced the induction of bladder tumors by BBN.

Extrapolation of cellular and molecular level studies to the human situation

This presentation deals with aspects of extrapolation in the areas of carcinogenesis and mutagenesis. Although many chemicals are known to induce cancer in experimental animals, relatively few are recognized with certainty as carcinogenic in humans. A large number of N‐nitroso compounds are potent carcinogens in animals and are useful models for extrapolation, although they are not proved human carcinogens. Prediction of carcinogenic activity from chemical structure is possible in some cases but is not generally reliable. Most carcinogens require metabolic activation by microsomal mixed‐function oxidases, and phenobarbitone, an inducer of these enzymes, produces tumors of mouse liver similar to those produced by some organochlorine pesticides. Epidemiological studies in humans indicate that prolonged phenobarbitone intake does not significantly increase the incidence of any human tumor except in the brain. Liver tumor induction in mice may be markedly influenced by relatively small environmental changes. ...

Inhibition by L-ascorbate of bacterial mutagenesis induced by two N-nitroso compounds

MANY chemicals are activated to carcinogens and mutagens by oxidative metabolism to alkylating agents1. Ascorbic acid has been reported to protect against tumour induction in mice by 3-hydroxyanthranilic acid, which induced bladder tumours2 and 7,12-dimethylbenzanthracene plus croton oil which induced skin tumours3. Ascorbic acid can also prevent the formation of carcinogenic N-nitroso compounds from nitrite and amines, in vivo4 and in vitro5. I report here that mutagenesis by two preformed N-nitroso compounds is effectively inhibited by ascorbic acid.

Genetics of murine sarcoma virus (MSV)--induced tumors in AKR mice: Evidence that late progressing and early regressing tumors are controlled by different gents.

The genetics of late appearing MSV tumors showing a progressive growth pattern in AKR mice was investigated. The late MSV tumor response in F1 hybrids depended on the genetic background of the non-AKR parent. Within the 4-month observation period following virus injection, (CBA X AKR) F1, (DBA/2 X AKR)F1, and (NIH X AKR)F1 developed progressing MSV tumors, which exhibited latency and growth behavior comparable to that seen in AKR mice, (BALB X AKR)F1, (B6 X AKR)F1, and (B10br x akr)f1 mice did not show any late MSV tumors. In contrast to early regressing M-MSV tumors, whose development is independent of Fv-1 genotype, late MSV tumor progression is largely a function of this gene, since all late tumors which appeared in (B10BR x AKR) x AKR were observed in Fv-1n homozygous mice, H-2k halotype is a further factor in the occurrence of late MSV tumors, at least in (B6 x AKR) x AKR mice. In crosses of AKR with Fv-1 compatible mice, tumor appearance was strongly associated with inheritance of AKR-Mulv, and MSV recovered from late tumors of first back-cross animals appeared to be a new pseudotype with the endogenous AKR-MuLV. It is suggested that the host genetic control in both early and late MSV tumors is exerted mainly on the helper component of the leukemia-sarcoma complex.

Induction of malignant skin tumors in mice by topical application of ethylnitrosourea.

A high percentage of squamous cell carcinomas were induced in the skin of Swiss-Webster mice by repeated topical application of ethylnitrosourea, indicating that this nitrosamide possesses a potent carcinogenic action when topically applied.

Effects of C. parvum on growth and induction of intracerebral tumours in mice.

An investigation was made into the effect of Corynebacterium parvum therapy on cerebral tumours in mice. I.v. C. parvum caused a slight but significant increase in the survival of BALB/c mice injected intracerebrally (i.c.) with not more than 50 Meth A cells. C. parvum was most effective if given on the same day or 5 days after tumour. If this interval was increased there was no effect. Multiple i.v. injections were no more effective than a single dose. I.v. C. parvum had no influence on the survival of C57BL mice injected i.c. with Lewis tumour cells, and had little effect on the induction of i.c. or s.c. tumours by methylcholanthrene. It was concluded that C. parvum therapy was of little use in the treatment of cerebral tumour in mice. The clinical implications of these findings are discussed.

Induction of lung tumors in mice with diamylnitrosamine

Mice of the CC57W strain were treated subcutaneouly with diamylnitrosoamine in a dose of 0.025 ml per mouse. once a week, 17 doses in all. These mice were sacrificed 27 weeks after the beginning of the experiment. Lung tumours, mainly adenomas, and in 3 cases adenocarcinomas, were detected in 14 of 17 mice which died and in 24 sacrificed mice. Besides, a marked proliferation of the interstitial tissue of the kidneys in a pretumor state, nephroblastoma, carcinoma in situ, and invasive cancer of the urinary bladder, one of each tumour, were found. Thus, diamylnitrosoamine can be recommended for induction of experimental lung tumours in mice.

Epidermal growth factor enhancement of skin tumor induction in mice.

Subcutaneous injection of epidermal growth factor 1. significantly shortened the latency period for the appearance of methylcholanthrene induced skin tumors and 2. increased the average number of papillomas elicited per mouse in both the Swiss Webster and C3HeB/FeJ strains.

H-2-like specificities of foreign haplotypes appearing on a mouse sarcoma after vaccinia virus infection.

ATTENTION has focused recently on the interaction of viruses and histocompatibility antigens, and it has been proposed that this relationship may be central to immune surveillance1–3. We report here the new expression of H–2 specificities apparently of other haplotypes on the surface of a chemically induced mouse tumour cell line following vaccinia virus infection.

Carcinogenic effect of N-butyl-N-nitrosourethan on CDF1 mice.

Studies were made on the induction of tumors in mice by N-butyl-N-nitro-sourethan (BNUR), with the following results. 1) Oral administration of 0.04% BNUR in deionized water to CDF1 mice for 20 weeks produced papillomas in the esophagus and forestomach of all 58 mice, and 24 of the mice had squamous cell carcinoma. 2) No skin tumors developed when 0.1%, 0.5%, or 1% BNUR in acetone was painted on the skin on the back of CDF1 mice three times a week for 25 weeks. 3) No sarcomas developed within 30 weeks when a dose of 10, 60, or 120 mg/ml of BNUR in dimethyl sulfoxide solution was injected subcutaneously into the back of CDF1 mice, 10 times at 1-week intervals. 4) In the in vitro malignant transformation test, golden hamster lung fibroblast cells did not show malignant transformation during an observation period of 150 days after treatment with BNUR at a final concentration of 30 and 60 mug/ml for 24 hr. The carcinogenicity and possible mode of action of BNUR are discussed on the basis of these results.