Lung tumour incidence in mice treated with hydrazine sulphate

Lung tumour incidence in mice fed with hydrazine sulphate (1.1 mg/day/mouse) was studied in male and female mice of Swiss, Strong “A” and F₁ cross of ICRC (female) × C3H (Jax) (male), as well as in C17 males. Swiss strain mice showed 100% lung adenocarcinomas. None of the treated mice of different strains had liver tumours. Hydrazine sulphate also induced adenocarcinomas of lung in Strong “A” and F₁ cross of ICRC females × C3H (Jax) males but it produced lymphomas of lung in C17 strain. Female mice of Swiss strain and F₁ hybrids showed greater susceptibility to hydrazine sulphate than the males. It was interesting to observe that protein and vitamin B deficiency in the diet shortened the tumour induction period in Swiss strain mice.     

Carcinogenicity of diethylnitrosamine in vitamin-A-deficient mice

The effect of suboptimal levels of dietary vitamin A on diethylnitrosamine (DEN) carcinogenesis was studied in BALB/c and Swiss mice. Two different dietary regimens were employed to induce vitamin A deficiency and DEN was administered by gavage at 2 dose levels: 0.6 mg/kg as a single dose and 200 mg/kg in 4 divided doses. Shark liver oil (SLO) which was the main source of vitamin A in the standard diet, was deleted in one regimen and reduced to 25% in the other. The mice maintained on the former diet were given a high dose of DEN and those on the latter diet received a low dose. In both strains the deficient mice had a greater tumour incidence than those on standard diet with a marginal reduction in the latent period. At the low level of DEN there was shift in organotrophy, i.e. from liver in controls to lung in the vitamin-A-deficient mice of BALB/c strain. With the higher dose, lung adenomas predominated in deficient as well as control groups in both the strains. Forestomach carcinomas appeared in deficient mice and not in the controls.     

Carcinogenic and cocarcinogenic potential of cypermethrin on mouse skin

Cypermethrin (CYM), a synthetic pyrethroid insecticide, is used widely because of its high bio-efficacy and low mammalian toxicity. In the present set of investigations, CYM has been evaluated for it's carcinogenic and co-carcinogenic (tumour initiating and tumour promoting) potential in mouse skin model of carcinogenesis. The results revealed that CYM possess complete carcinogenic as well as tumour initiating and promoting potential in both the sexes of Swiss albino mice. At the end point, i.e. 32 weeks in a single dose (10 mg/kg body weight (wt.), once only), initiated mice, 9 out of 12 surviving males, and 10 out of 14 surviving females developed benign tumours, while a higher incidence of tumourigenesis was recorded in multiple dose-initiated (10 mg/kg body wt., total nine applications) group, where 7 out of 9 surviving male and 10 out of 13 surviving female mice developed tumours at the site of topical exposure. The application of CYM as a tumour promoter on 7,12-dimethylbenz(a)anthracene initiated animals induced tumour incidence in about 4 out of surviving 10 male and 5 out of surviving 13 female Swiss albino mice. CYM when tested for complete carcinogenic activity induced tumour formation in both male and female animals at all the three tested dose levels.     

Effect of antioxidants and antitoxicants of isoniazid on the formation of lung tumours in mice by isoniazid and hydrazine sulphate

The present study reports the effects of antioxidants and antitoxicants on the formation of lung tumours in Swiss mice induced by isoniazid (INH) and hydrazine sulphate (HS).Dietary administration of butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) or simultaneous oral administration of antitoxicants (l-arginine, l-sodium glutamate and pyridoxine hydrochloride) failed to prevent HS-induced lung tumours. On the other hand BHA and BHT inhibited the formation of lung tumours in groups of mice receiving INH. Folic acid supplementation had marginal effect on the formation of lung tumours in groups receiving HS (P < 0.1).Higher lung tumour incidence was observed in groups maintained only on BHT diet as compared to animals maintained on standard diet.     

Modification by ozone of lung tumor development in mice

Mice, either strain A/J or Swiss Webster, were exposed for 18 weeks either to filtered air or to 0.4 or 0.8 ppm ozone for 8 hours daily. Subgroups in each test group received a single ip injection of 1,000 mg urethan/kg or 0.9% sodium chloride vehicle 1 day prior to initiation of the exposure regimen. Tumor incidence in Swiss Webster mice was 0-3% in groups not receiving urethan and was 61-74% in groups receiving urethan. In A/J mice, the corresponding values were 9-38% and 100%, respectively. Exposure to ozone caused a decrease in the number of tumors per lung in urethan-treated mice of both strains, in a dose-dependent manner. There seemed to be a specific decrease in tumors derived from alveolar type II cells in the A/J mice given urethan plus ozone. Most interesting, perhaps, was a significant increase in the number of tumors per lung in A/J mice exposed to 0.8 ppm ozone without urethan, confirming a previous report by others. The corresponding ozone effect on lung tumor development was not observed in Swiss Webster mice.     

Tumorigenic effect of thioacetamide in Swiss strain mice

Male and female Swiss strain mice were put on a 0.03% thioacetamide diet at the age of 2 months. Control mice were kept on a stock diet. Control and treated mice were killed at the ages of 6, 9, 13 and 17 months. Progressive morphological, histological and biochemical alterations in the liver and tumour tissue of the treated mice were studied. In the 17-month-old group, 12 out of 13 treated mice developed hepatomas.     

Carcinogenicity studies on the two tobacco-specific N-nitrosamines, N'-nitrosonornicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone

The tobacc-specific N-nitrosamines (TSNA) have been implicatedin oral cancer. However, except for one study using rats, nostudy has shown the ability of TSNA in inducing oral tumoursin experimental animals. We have studied the carcinogenic potentialsof N'-nitrcssonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone(NNK) in mice and hamsters, wherein the nitrosamines were administeredon the tongues of the mice and the cheek pouches of the hamstersto simulate the exposure conditions of humans. It was observedthat in Swiss and BALB/c male mice, both NNN and NNK inducedtumours of lung, forestomach and liver. However, no oral tumourswere induced in mice. The effect of vitamin A depletion wastested in Swiss male mice. It was found that a low vitamin Astatus did not alter the percentage incidence of tumours inducedby both nitrosamines to a significant extent. In the studiesusing Syrian golden hamsters, long-term treatment of NNK tohamster cheek pouch induced tumours in the lung, liver, stomachand cheek pouch. Subsequently, the effed of hydrogen peroxide(H₂O₂) on NNK-induced carcinogenicity in hamsters was studied.It was observed that simultaneous administration of NNK andH₂O₂ to the animals increased the incidence of cheek pouch tumours.Another pertinent observation was that even whena small initiatordase of NNK was given followed by the application of H₂O₂, avery significant increase in the tumour incidence was observed.This observation suggeststhat H₂O₂ could act as a promoter toNNK-induced carcinogenesis. In conclusion it may be stated thatboth NNN and NNK do not show any strain or species specificity.They failed to produce tumours at the site of application inmice but in hamsters few cheek pouch turnours were seen or wereinduced when NNK was applied alone. The cheek pouch tumour incidenceincreased when H₂O₂ was given concurrently or when applied fora long period after a low initiator dose of NNK was administeredin the cheek pouch.     

Carcinogenic and cocarcinogenic studies with carbaryl following topical exposure in mice.

Carbaryl (1-naphthyl methyl carbamate: C12H11NO2) CAS Reg. No. 63-25-2) is a widely used broad spectrum carbamate insecticide known to exert various toxic effects on experimental animals. Along with various other toxicological effects carbaryl is reported to increase the incidence of neoplasm in various tissues in rats after oral or intraperitoneal administration. No study has so far been reported in rodents to assess its carcinogenic/cocarcinogenic potential after topical exposure. In this set of investigations, the complete carcinogenic, tumour initiating and tumour promoting property of carbaryl was tested on the skin of female Swiss albino mice. The animals were exposed to carbaryl through topical painting on the interscapular region at a dose of 100 mg/kg body wt. The results revealed that carbaryl has tumour initiating potential, at the test dose, on mouse skin following two stage, initiation-promotion protocol, but, it failed to induce the tumour(s) when tested for complete carcinogenic and tumour promoting properties.     

Chemopreventive and Anticarcinogenic Effects of MomordicaCharantia Extract

The aim of the study was to examine whether Momordica fruit extract (MFE) and Momordica leaves extract(MLE) might exert any chemopreventive effect in a two stage protocol in skin carcinogenesis with Swiss albinomice. The tumour incidence, tumour yield, tumour burden and cumulative no. of papillomas were found to behigher in the controls (without either extract) as compared to the MFE or MLE treated experimental groups. Ina melanoma model, the mice which received fruit and leaf extracts of Momordica at the doses of 500 and 1000mg/kg body weight for 30 days showed increase in life span of animals and tumour volume was significantlyreduced as compared to control values. In cytogenetic studies, a single application of Momordica extracts atdoses of 500, 1000 and 1500 mg/kg body weight, 24 hours prior the i.p. administration of cyclophosphamide,significantly prevented micronucleus formation and chromosomal aberrations in a dose dependent manner inbone marrow cells of mice. The present study demonstrate chemopreventive potential of Momordica fruit andleaf extracts on DMBA induced skin tumorigenesis, melanoma tumour and cytogenicity.     

Evaluation of carcinogenic and co-carcinogenic potential Quinalphos in mouse skin

Quinalphos [O,O-diethyl-O-quinoxalinyl-phosphorothidate] is an organophosphorus pesticide with tremendous utility in mixed pest control due to its insecticidal and acaricidal properties. Apart from its pesticidal property, Quinalphos is known to induce various toxic effects in nontarget species and experimental animals. No studies have been conducted to evaluate the carcinogenic/co-carcinogenic hazards associated with Quinalphos exposure. In the present set of investigations, the tumorigenic potential of Quinalphos has been evaluated following topical exposure in Swiss albino mice. Long-term animal bioassays conducted for the evaluation of complete carcinogenic, tumour-initiating and tumour-promoting potential of Quinalphos revealed that it has only tumour-initiating potential at a dose of 10 mg/kg body weight (b.wt.), in the two-stage mouse skin model of carcinogenesis. Quinalphos exposure failed to produce neoplasia when tested for complete carcinogenic activity at all three tested dose levels or tumour promoting activity.     

Induction of bladder tumours in the mouse by direct implantation of 20-methylcholanthrene. (author's transl)]]

Plain paraffin was pellets and pellets containing 1% and 5% 20-MCA were implanted in the bladder of 219 C57 X IF and Swiss mice of both sexes. One hundred and fifty four survived and were killed after 40-42 weeks; 56 had been implanted with plain pellet and 98 with pellet containing the carcinogen. Only one bladder tumour (1,8%) developed in the former, whereas 35 tumours (35.7%) were found in the latter group. When a pellet containing 20-MCA was used, the tumour incidence was related to the strain and sex of the animals, rather than to the amount of carcinogen in the pellet. As a matter of fact, irrespective of the concentration of 20-MCA, females C57 X IF gave a significantly higher tumour yiels (87.5%) than males and Swiss mice of both sexes. It is concluded that when bladder implantation is used to induce tumours in mice, the results must be strictly referred to strain and sex. Besides tumours, areas of marked epithelial hyperplasia were seen in bladders implanted with either plain pellet or pellet containing 20-MCA. The possible meaning of this hyperplasia is briefly discussed and the need for further investigation stressed.     

Amelioration of radiation-induced hematological and biochemical alterations by Alstonia scholaris (a medicinal plant) extract

The radioprotective efficacy of a hydro-alcoholic extracted material from the bark of Alstonia scholaris (ASE) was studied in mice against radiation-induced hematological and biochemical alterations. Swiss albino mice were administered ASE (100 mg/kg body weight/d for 5 consecutive day) orally prior to whole-body gamma irradiation (7.5 Gy). Radiation exposure resulted in a significant decline (P<.001) in erythrocytes and hemoglobin until the third day, following a gradual recovery (ie, day 7), but these values did not reach normal values during the remainder of the animals' life span. Hematocrit percentage declined significantly (P<.001) until day 15. In contrast, ASE-pretreated irradiated animals had significantly higher erythrocyte, hematocrit, and hemoglobin values than the irradiated controls. Furthermore, a significant elevation in lipid peroxidation level over normal was recorded in gamma-irradiated mice, whereas this increase was considerably lower in ASE-pretreated animals. Pretreatment with ASE caused a significant increase in glutathione levels in serum as well as in liver in comparison to irradiated animals. This study showed that ASE protects against radiation-induced hematological and biochemical alterations in Swiss albino mice.     

The influence of the thymus on the development of transplanted mammary tumour in mice

The influence of thymectomy and the grafting of additional thymuses on the development of syngeneic mammary tumour has been studied in high cancer C3H/He strains of mice. The effect on the development of the grafted tumour of replacement of the thymus of F1 hybrid mice (C3H/HexC57BL) by thymus derived from donors of the parental streins has also been investigated. In C3H/He mice thymectomized on the 3rd day after birth the development of mammary tumour grafted at the age of 2 months was delayed. One or three additional syngeneic thymuses from 1-month-old donors grafted subcutaneously to C3H/He mice stimulated the development of grafted tumours, whereas inhibition of tumour development was observed in mice grafted with five additional thymuses. The replacement of the thymus in F₁ hybrid mice (C3H/HexC57BL) at the 5th day after birth by thymus of 5-day-old donors of low cancer C57BL strain led to the inhibition of mammary tumour grafted to mice at 2-3 months of age, while the replacement of the hybrid thymus by that obtained from donors of the high cancer C3H/He strain had no inhibitory effect. The data presented have been interpreted as evidence for genetically determined differences in the functional specificity of the thymus concerning its influence on malignant growth in high and low cancer strain mice. It is suggested that hereditary predisposition to malignant growth is, in particular, related to the functional properties of the thymus in high cancer strains of mice.     

The effect of connexin32 null mutation on hepatocarcinogenesis in different mouse strains.

Connexin32 (Cx32) is the major gap junctional protein in mouse liver. We have shown recently that the formation of liver tumours in Cx32-deficient mice is strongly increased in comparison with control wild-type mice, demonstrating that the deficiency in gap junctional communication has an enhancing effect on hepatocarcinogenesis. We have now compared the effect of Cx32 deficiency on liver carcinogenesis in two strains of mice with differing susceptibility to hepatocarcinogenesis. Heterozygous Cx32(+/-) females were crossed with male Cx32 wild-type C57BL/6J (low susceptibility) or C3H/He (high susceptibility) mice. Since the Cx32 gene is located on the X-chromosome, the resulting F1 males segregated to the genotypes Cx32(Y/+) and Cx32(Y/-). Genotyping was performed by PCR-analysis using tail-tip DNA. Weanling male mice were i.p. injected with a single dose of N-nitrosodiethylamine and were killed 16, 21 or 26 weeks later. The number, volume fraction and size distribution of precancerous liver lesions characterized by a deficiency in the marker enzyme glucose-6-phosphatase were quantitated. The results demonstrate that Cx32 deficiency only slightly affects the number of enzyme-altered lesions, but strongly enhances their growth, both in the resistant and the susceptible mouse strain, suggesting that decreased intercellular communication results in tumour promoting activity irrespective of the genetic background of the mouse strain used. Since Cx32-deficient C3H/He hybrids were approximately 5-10 times more sensitive than C3H/He hybrids with an intact Cx32 gene, this mouse strain may prove very useful for toxicological screening purposes.     

Antiproliferative effect of methyl-beta-cyclodextrin in vitro and in human tumour xenografted athymic nude mice.

The anti-tumour activity of methyl-beta-cyclodextrin (MEBCD), a cyclic oligosaccharide known for its interaction with the plasma membrane, was investigated in vitro and in vivo and compared with that of doxorubicin (DOX) in the human tumour models MCF7 breast carcinoma and A2780 ovarian carcinoma. In vitro proliferation was assessed using the MTT assay. In vivo studies were carried out using xenografted Swiss nude mice injected weekly i.p. with MEBCD at 300 or 800 mg kg(-1) or DOX at 2 mg kg(-1), during 2 months. Under these conditions, MEBCD was active against MCF7 and A2780 cell lines and tumour xenografts. For each tumour model, the tumoral volume of the xenografted mice treated with MEBCD was at least twofold reduced compared with the control group. In the MCF7 model, MEBCD (800 mg kg(-1)) was more active than DOX (2 mg kg(-1)). After 56 days of treatment with MEBCD, no toxicologically meaningful differences were observed in macroscopic and microscopic parameters compared with controls. The accumulation of MEBCD in normal and tumour tissues was also assessed using a chromatographic method. Results indicated that after a single injection of MEBCD, tumour, liver and kidneys accumulated the highest concentrations of MEBCD. These results provided a basis for the potential therapeutic application of MEBCD in cancer therapy.     

Anti-tumour effect of UFT on human renal cell carcinoma heterotransplanted into nude mice

1) Using two histologically different human renal cell carcinomas heterotransplanted into nude mice, the antitumour effect of UFT was investigated, and an attempt was made to analyze the properties of the tumour strains where a drug efficacy was noted. 2) The two strains used were the JRC 1 strain (tumour doubling time of 9.4 days, clear cell type, papillary histologic pattern, grade 3) and the JRC 11 strain (tumour doubling time of 2.72 days, granular cell type, anaplastic histologic pattern, grade 4). 3) Two dose groups were set up, one receiving 10 mg/kg of tegafur (FT) and 22.4 mg/kg of uracil and the other receiving 20 mg/kg of FT and 44.8 mg/kg of uracil. Each group was further divided into an early administration group (start of administration 3 days after the tumour transplantation) and a late administration group (start of administration at a time when the transplanted tumour proliferated to weight of 100 to 300 mg). 4) Effect as noted in the tumour proliferation inhibition rate was seen only in the group receiving 20 mg/kg of FT and 44.8 mg/kg of uracil in both early and late administration groups of the JRC 1 strain. Among these groups only the early administration groups showed a histological positive effect. 5) The fact that the measured 5-FU intra-tumour concentration in the JRC 1 strain was only 1/4 that of the JRC 11 strain demonstrates more susceptibility of JRC 1 strain to UFT. Moreover, intratumoral concentration of 5-FU differed markedly even with the same administration method and dosage level. This result indicates that intra-tumour concentration will be different if the histological pattern differs.     

Effect of nicotinamide on hepatic microsomal drug metabolising system in tumour-bearing rats and mice

Administration of nicotinamide to Wistar rats (100 mg/kg body wt.) bearing Yoshida sarcoma (ascites) tumour as well as to Swiss and CBA mice (250 mg/kg body wt.) bearing the transplantable fibrosarcoma and the spontaneously induced mammary carcinoma, respectively, was shown to bring about a reversal of the decreased activity of NADPH-cytochrome c reductase in host livers of the tumour-bearing animals. Nicotinamide injection was also shown to bring about a significant increase in the levels of host hepatic cytochromes P-450 and b5 and in the activities of aminopyrine demethylase and UDP-glucuronosyl transferase which were shown to be low in the tumour-bearing rats. Treatment with nicotinamide was shown to be equally effective in reversing the inhibited activities of hepatic drug metabolising enzymes observed in healthy adult rats injected with serum from the tumour-bearing rats. Administration of nicotinamide to adult male rats brought about an increased incorporation of [14C]leucine in hepatic microsomal proteins which was insensitive to inhibition by actinomycin D at a dose of 1 mg/kg body wt. but could be inhibited by the antibiotic at a lower dose of 0.1 mg/kg body wt. as well as by cycloheximide.     

Evaluation of Anticarcinogenic and Antimutagenic Potential of Bauhinia variegata Extract in Swiss Albino Mice

Background: Infusions from the bark of Bauhinia is used to treat various diseases in the traditional medicalsystem of India and decoction of the roots is used in dyspepsia and act as an antidote to snake poison. Itschemopreventive potential for cancer was the subject of the present study. Materials and methods: To evaluatethe anticarcinogenicity and antimutagenicity of Kachanar extract a skin carcinogenesis and melanoma tumourmodel was used, along with micronucleus and chromosomal aberration tests, in Swiss albino mice. Results: Inthe skin papilloma model, significant prevention, with delayed appearance and reduction in the cumulative no.of papillomas was observed in the DMBA + Kachanar + croton oil treated group as compared to the DMBA +Croton Oil group. C57 Bl mice which received a 50 % methanolic extract of Kachanar extract at the doses of500 and 1000 mg/ kg body weight for 30 days showed increase in life span and tumour size was significantlyreduced as compared to controls. In antimutagenicity studies,a single application of Kachanar extract at dosesof 300, 600 and 900 mg/kg dry weight, 24 hours prior the i.p. administration of cyclophosphamide (at the 50 mg/kg) significantly prevented micronucleus formation and chromosomal aberrations in bone marrow cells ofmice, in a dose dependent manner. Conclusions: Our results suggest that Kachanar extract exerts anticarcinogenicand antimutagenic activity.     

Cytogenetic toxicity of cisplatin in bone marrow cells of Swiss mice

The inorganic platinum compound cisplatin (CP) in Oncoplatin, an anticancer drug, as the test chemical and cyclophosphamide (CY) in Endoxan, another anticancer drug, as the positive control, were tested for their cytogenetic toxicity in bone marrow cells of Swiss mice. The end points selected were mitotic metaphase chromosomal aberration and mitotic index study at 24-hour post-treatment and micronucleus test at 30-hour post-treatment after a single intraperitoneal exposure. The doses of the chemicals tested were CP 2, 3 and 5 mg/kg and CY 40 mg/kg b.w. of mice. Each of the doses of CP induced a significant number of chromosomal aberrations, mostly chromatid breaks and fragments and a significant number of micronuclei. The mitotic index study indicated CP as nonmitotoxic. The female mice were found more sensitive to each of the doses of CP than the males by showing more chromosomal aberrations, a higher number of micronuclei and comparatively less percentages of dividing cells. CP was thus found to be highly clastogenic in bone marrow cells of Swiss mice.     

Mouse skin carcinogenicity tests of the flame retardants tris(2,3-dibromopropyl)phosphate, tetrakis(hydroxymethyl)phosphonium chloride, and polyvinyl bromide

The flame retardants tris(2,3-dibromopropyl)phosphate, tetrakis(hydroxymethyl)phosphonium chloride, and polyvinyl bromide were tested for carcinogenic activity by skin application 3 times weekly in random-bred female ICR/Ha Swiss mice for 420 to 496 days. Tris(2,3-dibromopropyl)phosphate at two dose levels (30 mg and 10 mg/application) induced benign and malignant tumors of the skin, forestomach, and oral cavity (tongue and gingiva) in a statistically significant number of mice (30/group). A statistically significant incidence of papillary tumors of the lung was observed at both dosages, and the higher dose also resulted in one mouse with a tubular adenoma of the kidney. Tetrakis(hydroxymethyl)phosphonium chloride (2 mg/application, 60 mice) and polyvinyl bromide (0.1 ml latex suspension/application, 30 mice) were inactive. Polyvinyl bromide was also injected s.c. into another group of female ICR/Ha Swiss mice once weekly for 48 weeks, and the mice were observed for a total of 60 weeks. Liposarcomas were induced in 19 of 30 mice, which was ascribed to physical carcinogenesis. Appropriate solvent and no-treatment control groups were included.