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M Futakuchi

Publications and source records attributed to M Futakuchi.

At least 19 recordsLinked to original sources
PubMed2002

Organ differences in the enhancing potential of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine on carcinogenicity in the prostate, colon and pancreas.

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), the most abundant carcinogenic heterocyclic amine in cooked meat and fish, is speculated to be associated with human carcinogenesis. It has been shown to induce DNA adducts in a variety of organs in rodents and thus clarification of any enhancement of neoplasia is a very important subject for assessing human risk. In order to evaluate modifying effects of PhIP on carcinogenesis, several in vivo experiments in rats were performed. These featured dietary administration of PhIP at different dose levels and for different durations, and included intragastric dosing for a short period, or continuous dietary administration after initiation with other carcinogen, namely 3,2'-dimethyl-4-aminobiphenyl (DMAB) or 1,2-dimethylhydrazine (DMH). The data indicate that a short administration of PhIP is sufficient to induce prostate tumors but long-term treatment is required for effects in the colon. They also suggest tumor enhancing potential dependent on the organ, i.e. evident in the colon but not the prostate. Furthermore, promotion of colon neoplasia may depend on the initiator employed. Thus these findings suggest that the carcinogenic mechanisms of PhIP may vary in its different target organs.

1,2-Dimethylhydrazine↗
PubMed2001

Site-dependent modulating effects of conjugated fatty acids from safflower oil in a rat two-stage carcinogenesis model in female Sprague-Dawley rats.

Modifying effects of dietary administration of conjugated fatty acids from safflower oil (CFA-S), rich in conjugated linoleic acid, on major organs were examined in the post-initiation stage of a two-stage carcinogenesis model in female rats. Groups of 21 or 22 F344 female rats were treated sequentially with 2,2'-dihydroxy-di-n-propylnitosamine (intragastrically, i.g.), 7,12-dimethylbenz[a]anthracene (i.g.), 1,2-dimethylhydrazine (subcutaneously) and N-butyl-N-(4-hydroxybutyl)nitrosamine (in drinking water) during the first 3 weeks for initiation, and then administered diet containing 1 or 0.1% CFA-S for 33 weeks. Further groups of animals were treated with carcinogens or 1% CFA-S alone, or maintained as non-treated controls. All surviving animals were killed at week 36, and major organs were examined histopathologically for development of pre-neoplastic and neoplastic lesions. The 1 and 0.1% CFA-S treatment significantly decreased the incidence and multiplicity of mammary carcinomas, though a clear dose response was not observed. In the urinary bladder, the incidence of papillary or nodular hyperplasia but not tumors was significantly increased in the 1% CFA-S-treated group. The results indicate that low dose CFA-S may find application as a potent chemopreventor of mammary carcinogenesis.

1,2-Dimethylhydrazine↗
PubMed2001

Establishment of rat hepatocellular carcinoma cell lines with differing metastatic potential in nude mice.

For better understanding of cancer metastasis, we have established an in vivo model for induction of highly metastatic hepatocellular carcinomas (HCC) in male F344 rats. From 1 tumor, 4 cell lines with differing metastatic potential (C1, C2, C6, C5F) were established by subcloning using the limited-dilution cloning technique. Two other lines, N1 and L2, arose from another primary HCC and a lung metastatic lesion, respectively. Although cell adhesion of each cell line in culture medium was different, tumors developing in the subcutis of nude mice after transplantation were all moderately differentiated HCC with a trabecular pattern. On subcutaneous injection into nude mice, all 6 cell lines proved to be tumorigenic in the injection site and C5F was highly metastatic to the lung. With injection into the tail vein, N1 and L2 formed frequent metastases in the lung as well as in lymph nodes. Using intraperitoneal injection, C1, C6, N1 and L2 showed marked disseminated growth in the abdominal cavity with bloody ascitis. Northern blot analysis revealed expression of known metastasis-related genes, KAI1 and heparanase, to be decreased in C5F, but no differences in expression of nm23-H1 were evident. A point mutation in the GSK-3beta phosphorylation site of the beta-catenin gene was found in L2. These transplantable HCC cell lines that have different metastatic ability should be useful for elucidation of mechanisms of metastasis.

Animals↗
PubMed2001

Organ dependent enhancement of rat 3,2'-dimethyl-4-aminobiphenyl (DMAB) carcinogenesis by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP): positive effects on the intestine but not the prostate.

In order to evaluate tumor enhancing effects of the heterocyclic carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), doses of 100 and 300 p.p.m. PhIP were given for 40 weeks to male F344 rats, which initially received 3,2'-dimethyl-4-aminobiphenyl (DMAB). DMAB shows a similar carcinogenic organ spectrum to that of PhIP, including the prostate and colon. PhIP alone at a dose of 300 p.p.m. resulted in the development of prostate and intestine cancers. Furthermore, among the DMAB-treated group, enhancement of intestinal carcinogenesis by 300 p.p.m. PhIP was observed. However, no prostate enhancement was demonstrated in the DMAB + PhIP group. Since PhIP-DNA adduct formation in the prostate epithelial cells in a satellite experiment was not affected by pre-treatment with DMAB, it is speculated that the contradictory findings between the intestine and prostate may be due to the specific biological effects of PhIP. Taking into account previous data, that PhIP clearly enhanced rat 1,2-dimethylhydrazine-initiated colon tumorigenesis, the potential of PhIP to enhance colon carcinogenesis may be initiator dependent.

Aminobiphenyl Compounds↗
PubMed2000

Enhancing effects of Thai edible plants on 2-amino-3, 8-dimethylimidazo(4,5-f)quinoxaline-hepatocarcinogenesis in a rat medium-term bioassay.

Boesenbergia pandurata (Zingiberaceae), Languas galanga (Zingiberaceae) and Citrus hystrix (Rutaceae) are edible plants that are commonly used as flavors or condiments in various Thai food dishes. They are known to exert strong anti-promoting activity in a test of tumor promoter-induced Epstein-Barr virus (EBV) activation. In the present study their effects on hepatocarcinogenesis were investigated in a medium-term bioassay using F344 male rats. C. hystrix significantly enhanced 2-amino-3,8-dimethylimidazo(4, 5-f)quinoxaline-associated preneoplastic liver cell focus development while B. pandurata and L. galanga had borderline effects. The results suggest that C. hystrix as well as B. pandurata and L. galanga may contain agents augmenting the hepatocarcinogenicity of 2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline.

Animals↗
PubMed2000

Effects of arctiin on PhIP-induced mammary, colon and pancreatic carcinogenesis in female Sprague-Dawley rats and MeIQx-induced hepatocarcinogenesis in male F344 rats.

Chemopreventive effects of arctiin, a lignan isolated from Arctium lappa (burdock) seeds, on the initiation or post initiation period of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) induced mammary carcinogenesis in female rats and on 2-amino-3, 8-dimethylimidazo[4,5-f]quinoxaline (MeIQx)-associated hepatocarcinogenesis in male rats were examined. In experiment 1, female Sprague-Dawley (SD) rats were given intragastric doses of 100 mg/kg body wt of PhIP once a week for 8 weeks as initiation. Groups of 20 rats each were treated with 0.2 or 0.02% arctiin during or after PhIP initiation. Control rats were fed 0.2 or 0.02% arctiin, or basal diet alone during the experimental period. Animals were killed at the end of week 48. Although the incidence of mammary carcinomas did not significantly differ among the PhIP-treated groups, multiplicity was significantly decreased in rats given 0.2 (0.7+/-0.7, P<0.05) or 0.02% (1.0+/-1.1, P<0.05) arctiin after PhIP initiation as compared with the PhIP alone controls (2.1+/-2.5). The average number of colon aberrant crypt foci was also significantly decreased in these two groups. Pancreas acidophilic foci were induced in PhIP treated animals with slight decrease in the multiplicity with arctiin during the initiation phase. For liver carcinogenesis, groups of 15 male F344 rats were given a single intraperitoneal injection of diethylnitrosamine (DEN) and starting 2 weeks later, they were administered 0.03% MeIQx in the diet, MeIQx together with 0.5% arctiin, 0.1% arctiin or basal diet for 6 weeks. They were subjected to two-third partial hepatectomy 3 weeks after DEN initiation and killed at the end of week 8 for glutathione S-transferase placental form (GST-P) immunohistochemistry. The numbers and areas of preneoplastic GST-P positive foci were elevated by the treatment with MeIQx, and further increased by the simultaneous treatment with arctiin. These results indicate that arctiin has a protective effect on PhIP-induced carcinogenesis particularly in the mammary gland in the promotion period. On the other hand, it may have a weak co-carcinogenic influence on MeIQx-induced hepatocarcinogenesis. In addition, the results suggested that PhIP is a weak pancreatic carcinogen in female SD rats, targeting acinar cells.

Animals↗
PubMed2000

Inhibitory effects of low doses of melatonin on induction of preneoplastic liver lesions in a medium-term liver bioassay in F344 rats: relation to the influence of electromagnetic near field exposure.

We have previously reported that exposures of F344 male rats to both 900 MHz and 1.5 GHz electro-magnetic near fields (EMFs) results in slightly decreased numbers and areas of glutathione S-transferase (GST-P)-positive liver foci, liver preneoplastic lesions in rats, in a medium-term liver bioassay (K. Imaida, M. Taki, T. Yamaguchi, T. Ito, S. Watanabe, K. Wake, A. Aimoto, Y. Kamimura, N. Ito, T. Shirai, Lack of promoting effects of the electromagnetic near-field used for cellular phones (929.2 MHz) on rat liver carcinogenesis in a medium-term liver bioassay, Carcinogenesis 19 (1998) 311-314; K. Imaida, M. Taki, S. Watanabe, Y. Kamimura, T. Ito, T. Yamaguchi, N. Ito, T. Shirai, The 1.5 GHz electromagnetic near-field used for cellular phones does not promote rat liver carcinogenesis in a medium-term liver bioassay, Jpn. J. Cancer Res. 89 (1998) 995-1002.). In both experiments, the melatonin serum levels were significantly decreased in both 900 MHz and 1.5 GHz exposed groups as compared with sham-exposed control group values. Therefore, changes of serum melatonin levels may modify the development of preneoplastic lesions in the livers of rats exposed by EMF. In order to clarify this question, the effects of different doses of melatonin (1, 5, 10 and 20 ppm in the drinking water) were analyzed in the same bioassay system employed for our previously reported EMF exposure studies. Six-week-old male F344 rats were given a single dose of diethylnitrosamine (DEN, 200 mg/kg b.w., i.p.). Starting 2 weeks later, they were treated with 0, 1, 5, 10 and 20 ppm melatonin in their drinking water for 6 weeks. Melatonin treatment were performed only during the night (between 18:00 to 09:00) in order to maintain their circadian rhythm, since serum melatonin levels are high at midnight. At week 3, all rats were subjected to a two-thirds partial hepatectomy. At week 8, the experiment was terminated and the animals were sacrificed. Serum hormone levels of melatonin, adrenocorticotropic hormone (ACTH), corticosterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH) and testosterone at this time point were measured, only the first being elevated, while LH and testosterone were reduced. Although clear dose dependence was not apparent, both numbers and areas of GST-P-positive foci in the liver were decreased in the melatonin treated groups, this being significant for numbers in the 10 ppm melatonin group. Comparison of the current results with the previously reported findings for EMF exposure experiments, suggests that increase in melatonin serum levels is a possible reason for the associated tendency for decreased preneoplastic hepatocyte foci development.

Adrenocorticotropic Hormone↗
PubMed2000

Experimental prostate carcinogenesis - rodent models.

A number of rodent models of prostate carcinoma development have been established to study mechanisms and modifying potential. All except for transgenic mouse models need long experimental periods for generation of a high yield of cancers. Spontaneous prostate tumor models, while not practical in terms of time and tumor incidences, allow the natural course of multistep neoplasia to be followed without a need for chemical exposure. Carcinogens, especially in combination with testosterone, can induce prostate carcinomas in rats, but none are prostate-specific, so that tumor development in other organs is a complicating factor. Induction of invasive prostate carcinomas in the rat frequently requires long-term administration of a pharmacological dose of testosterone with or without application of a chemical carcinogen. While there are several transgenic mouse models, each also has strong and weak points, and it is therefore necessary to select the best model for the purpose of any experimental study.

Aminobiphenyl Compounds↗
PubMed2000

Protective mechanisms against the intestinal nematode Strongyloides venezuelensis in Schistosoma japonicum-infected mice.

Mice infected with Schistosoma japonicum were resistant to the intestinal nematode, Strongyloides venezuelensis. The numbers of adult S. venezuelensis recovered from mice were significantly decreased when infections were given from 6 weeks after S. japonicum infection. Larval recovery from the lungs showed that significant numbers of subcutaneously inoculated S. venezuelensis larvae were eliminated by 3 days in S. japonicum-infected mice (P < 0.0001), while histology revealed that this was associated with massive eosinophilic infiltration in the lungs. In addition, adult S. venezuelensis worms implanted in the duodenum of S. japonicum-infected mice could not establish in the intestine. This failure was associated with mucosal mastocytosis. Activation of eosinophils and intestinal mast cells was correlated with elevated expression of mRNA for interleukin (IL)-3, IL-4, and IL-5 in S. japonicum-infected mice. Sera from S. japonicum-infected mice recognized S. venezuelensis larva antigens as strongly as those from S. venezuelensis-infected mice, although transfer of sera from S. japonicum-infected mice to normal recipient mice did not protect them from S. venezuelensis challenge infection. It was concluded that the mechanisms for larval killing and adult worm expulsion of S. venezuelensis in S. japonicum-infected mice were identical to those seen in infections with S. venezuelensis only.

Animals↗
PubMed2000

Suppressive effects of dietary genistin and daidzin on rat prostate carcinogenesis.

High intake of phytoestrogens through soybeans and their products is thought to be associated with low incidences of prostate and / or breast cancer in Asian countries. Possible chemopreventive effects of genistin or daidzin on rat prostate carcinogenesis were therefore investigated. Male F344 rats were given 10 biweekly subcutaneous injections of 3,2'-dimethyl-4-aminobiphenyl (DMAB) and then either genistin or daidzin in the diet at a concentration of 0.1% for 40 weeks. Other groups of rats given DMAB were treated with genistin or daidzin together with a high dose of testosterone propionate (TP). Both genistin and daidzin reduced the numbers of ventral prostate carcinomas (P < 0.05), with a tendency for decrease in incidence. Invasive carcinomas which developed in the anterior prostate and seminal vesicles with TP were, however, not influenced by the two isoflavones. Thus, the present data suggest that genistin and daidzin possess anti-cancer effects at relatively early stages of prostate cancer development, providing experimental support for epidemiological findings.

Aminobiphenyl Compounds↗
PubMed1999

Chemoprevention of heterocyclic amine-induced carcinogenesis by phenolic compounds in rats.

Chemopreventive effects of synthetic and naturally occurring antioxidants on heterocyclic amine (HCA)-induced rat carcinogenesis and mechanisms of inhibition were assessed. In a medium-term liver bioassay, combined treatment with 0.03% 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and synthetic antioxidants such as 1-O-hexyl-2,3,5-trimethylhydroquinone (HTHQ), BHA, BHT, tert-butylhydroquinone (TBHQ) and propyl gallate, each at a dose of 0.25%, and troglitazone at doses 0.5 and 0.1%, potently inhibited development of glutathione S-transferase placental form (GST-P) positive foci as compared with MeIQx alone values. Of these antioxidants, HTHQ showed the greatest activity. Green tea catechins tended to inhibit GST-P positive foci development, while quercetin, rutin, curcumin, daidzin, ferulic acid and genistin all exerted significant enhancing effects. HTHQ also inhibited 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-induced colon carcinogenesis in a two stage colon carcinogenesis model using 1,2-dimethylhydrazine (DMH) as an initiator. Immunohistochemically detected PhIP-DNA adduct positive nuclei in the colon induced by continuous oral treatment with 0.02% PhIP for 2 weeks decreased by the combined treatment with 0.5 or 0.125% HTHQ. Methoxyresorfin O-demethylase activity in rat liver microsomes in vitro was clearly inhibited by the addition of HTHQ, BHA, BHT, TBHQ or propyl gallate, with particularly strong inhibition being observed in HTHQ. However, the CYP1A2 level in rat liver increased after oral treatment with HTHQ for 2 weeks. These results indicate that synthetic antioxidants, HTHQ in particular, is a very strong chemopreventor of HCA-induced carcinogenesis. It is suggested that depression of metabolic activation rather than antioxidant activity is responsible for the observed effect. However, other mechanisms, including the effects on phase II enzymes cannot be ruled out.

Animals↗
PubMed1999

Carcinogenicity of 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP) in the rat prostate and induction of invasive carcinomas by subsequent treatment with testosterone propionate.

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) at 400 ppm in the diet for 52 weeks was found to induce non-invasive microscopic carcinomas in the ventral prostate of the treated rats, in addition to colon and mammary carcinomas. The current experimental data demonstrate that only a 20-week period of PhIP treatment is sufficient for induction of ventral carcinomas and that long-term pharmacological dosing with testosterone propionate which applied through a Silastic tube embedded in the subcutis after PhIP treatment can induce invasive carcinomas in the anterior prostate and seminal vesicles. Thus, PhIP may provide the basis for a good two stage carcinogenesis model for investigation of prostate carcinogenesis.

Animals↗
PubMed1999

Development of androgen-independent carcinomas from androgen-dependent preneoplastic lesions in the male accessory sex organs of rats treated with 3,2'-dimethyl-4-aminobiphenyl and testosterone propionate.

Two kinds of cancer can be induced in rat male accessory sex organs, one a non-invasive carcinoma arising in the ventral lobe and the other an invasive lesion which develops in the dorsolateral and anterior lobe as well as the seminal vesicles. In the present study, one group of male rats were given biweekly s.c. injections of 3,2'-dimethyl-4-aminobiphenyl (DMAB) for 20 weeks for induction of non-invasive carcinomas and the other group received DMAB with 40-week testosterone propionate for induction of invasive carcinomas. Half of the animals in each group were then subjected to bilateral orchiectomy at week 41 to remove testicular androgen, in order to examine the androgen dependence of both types of carcinomas as well as precancerous lesions. Animals were killed at weeks 41, 46 and 60. All parts of the prostate complex showed involution and significant weight reduction after castration, with a complete disappearance of atypical hyperplasias and carcinomas of the ventral prostate. However, in spite of suppression of development of atypical hyperplasias in the anterior prostate and seminal vesicles, the incidence of invasive carcinomas was not changed. Normal epithelial cells and atypical hyperplasias of all parts of the prostate and seminal vesicles and carcinomas of the ventral prostate were immunohistochemically positive for nuclear androgen receptor, while invasive carcinomas that developed in either castrated or non-castrated animals were negative. These findings suggest that in the ventral prostate, both precancerous and cancerous lesions are androgen-dependent, but in the anterior and seminal vesicles, cancerous lesions (invasive carcinomas) are androgen-independent while precancerous lesions are hormone-dependent.

Aminobiphenyl Compounds↗
PubMed1999

Establishment of an in vivo highly metastatic rat hepatocellular carcinoma model.

We previously found by chance that N-nitrosomorpholine (NMOR) given after a multi-carcinogenic treatment induces liver carcinomas with 56% lung metastasis, and it was confirmed that hepatocellular carcinoma (HCC) with 100% lung metastasis was produced by 24-week treatment with NMOR and additional treatment with diethylnitrosamine (DEN). In the present study, we modified the duration of NMOR to establish an animal model with a simple experimental protocol and an appropriate experimental duration which would facilitate further study of the mechanisms of metastasis and antimetastatic agents. The results revealed DEN exposure followed by a 16-week treatment with NMOR to be a most efficient method for the induction of HCC metastasizing to the lung. Loss of cadherin, demonstrated immunohistochemically, occurred in an early stage of carcinogenesis, and this was reflected in malignant conversion of primary lesions. This model, with its essential similarities to malignant tumor behavior in man, should find application not only for elucidation of the mechanisms underlying metastasis, but also in the development of anti-metastatic agents.

Animals↗
PubMed1998

Strong promoting activity of phenylethyl isothiocyanate and benzyl isothiocyanate on urinary bladder carcinogenesis in F344 male rats.

Post-initiation effects of phenylethyl isothiocyanate (PEITC) and benzyl isothiocyanate (BITC) on hepatocarcinogenesis and urinary bladder carcinogenesis were examined in rats pretreated with diethylnitrosamine (DEN) and N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN). Groups of 21 rats received a single intraperitoneal injection of 200 mg/kg body weight of DEN. Starting 2 days thereafter, they were administered 0.05% BBN in the drinking water for 4 weeks. Three days after completion of the carcinogen treatment, they were placed on a diet containing PEITC or BITC at a dose of 0.1%, or a basal diet alone for 32 weeks and then killed for autopsy. Further groups of 6 rats each were similarly treated with PEITC, BITC or basal diet alone for 32 weeks without prior DEN and BBN exposure. In the liver, although the incidences of liver tumors were not significantly affected, the multiplicity of foci larger than 0.5 cm in diameter was slightly increased by PEITC. In the urinary bladder, the incidences of papillary or nodular (PN) hyperplasias and carcinomas were significantly elevated by PEITC or BITC after DEN and BBN initiation. In the groups without initiation, PN hyperplasia was found in all rats of both PEITC and BITC groups, along with papillomas and carcinomas in some animals. Tumors and PN hyperplasias in the groups treated with PEITC and BITC are characterized by downward growth. Our results thus showed PEITC and BITC to be strong promoters of urinary bladder carcinogenesis with some complete carcinogenic potential.

Animals↗
PubMed1998

Stage and organ dependent effects of 1-O-hexyl-2,3,5-trimethylhydroquinone, ascorbic acid derivatives, n-heptadecane-8-10-dione and phenylethyl isothiocyanate in a rat multiorgan carcinogenesis model.

The effects of 1-O-hexyl-2,3,5-trimethylhydroquinone (HTHQ), phenylethylisothiocyanate (PEITC), 3-O-ethylascorbic acid, 3-O-dodecylcarbomethylascorbic acid and n-heptadecane-8, 10-dione were analyzed in a rat multiorgan carcinogenesis model. Groups of 15 animals were given a single intraperitoneal (i.p.) injection of diethylnitrosamine and 4 i.p. injections of N-methylnitrosourea as well as N-butyl-N-(4-hydroxybutyl) nitrosamine in the drinking water during the first 2 weeks. Then 4 subcutaneous (s.c.) injections of dimethylhydrazine and 2,2'-dihydroxy-di-n-propylnitrosamine were given in the drinking water over the next 2 weeks for initiation. Test compounds were administered during the initiation or post-initiation periods. The dietary dose was 1% except for n-heptadecane-8, 10-dione and PEITC (0.1%). Complete autopsy was performed at the end of experimental week 28. All 5 compounds reduced the number of lung hyperplasia, particularly PEITC when given during the initiation period. In addition, HTHQ lowered the incidence of esophageal hyperplasia in the initiation period, and of small and large intestinal adenomas in the post-initiation period. However, it also enhanced the development of hyperplasia and papilloma in the forestomach and tongue. PEITC lowered the induction of esophageal hyperplasia, kidney atypical tubules and liver glutathione S-transferase placental form (GST-P)-positive foci when given during the initiation period but enhanced the development of liver GST-P positive foci and urinary bladder tumors in the post-initiation period. Moreover, it induced hyperplasia of the urinary bladder. Our results indicate minor adverse effects for HTHQ in the forestomach and tongue, and demonstrate that PEITC, which inhibits carcinogenesis at the initiation stage in several organs, also exhibits promotion potential in liver and urinary bladder in the post-initiation stage under the present experimental conditions.

Animals↗
PubMed1998

Studies of initiation and promotion of carcinogenesis by N-nitroso compounds.

Complete carcinogens must possess both initiating and promoting properties. Most N-nitroso compounds are mutagens and are considered to be initiators, but some are not mutagenic and yet are complete carcinogens. To investigate the two activities, brief treatments of male F344 rats with each of three mutagens, nitrosodimethylurea, nitrosodiethylurea and nitrosobis-(2-oxopropyl)-amine, were followed by chronic treatment (40 weeks) with one of four non-mutagens, nitrosomethyl-3-carboxypropylamine, nitrosodiethanolamine, nitrosomethyl-2-hydroxypropylamine or phenobarbital, the last being a well-known promotor of liver tumors in rats. Each treatment group consisted of 18 animals and there were control groups of 15 animals without initiation and 15 animals without promotion. All surviving rats were sacrificed at week 78. There were almost no tumors in untreated controls or in groups treated with the promotors, other than bladder tumors in one group. Certain tumors were numerous in the initiated groups, but there were only a few instances of increased incidences after treatment with the promotors. The action of the initiators appeared to be the dominant factor and there was scant indication in this experiment of the induction of tumors by the promotors of promotion of initiated cells in most organs (e.g. the liver). This indicates that it is unlikely that non-genotoxic carcinogens induce tumors by promotion of already-initiated cells, but that some other mechanism prevails.

Animals↗