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PubMed1975

Inactivation of bacteriophages T7 and phiX174 by radiomimetics.

Inactivation of phages T7 and phiX174 induced by the radiomimetics N-nitroso-N-methylurea (NMU) and N-acetylethylenimine (AEI) has been studied. In semilogarithmic scale the kinetic curves of phage inactivation were steplike in character. This was connected with the occurrence of several processes in the system. A possible kinetic model has been proposed for the process of NMU-induced phage inactivation. The model is applicable to initial phage inactivation only. From the model a kinetic curve parameter, rho can be determined which characterizes the radiomimetic effect on different phages and determines the changes in the repair system after caffeine treatment. NMU exerted a post-inactivation effect on the phage T7. Also the NMU-induced phage T7 post-inactivation kinetic curves were of steplike character. They can be described as a sum of two exponential processes of different rate constant. The rate constant for the first stage of the post-inactivation process was close to the depurinization rate constant found in the literature.

Azirines↗

PubMed1983

N-nitroso-N-methylurea-induced mammary carcinogenesis: effect of pregnancy on preneoplastic cells.

The effect of pregnancy and lactation on mammary cancers induced with N-nitroso-N-methylurea (NMU) was determined in female outbred Sprague-Dawley rats. The animals received 5 mg NMU/100 g body weight at 50 days of age and were divided into the following groups: virgin, pregnancy (beginning 10 days after NMU administration), pregnancy and lactation (beginning 10 days after NMU), and pregnancy and lactation (beginning 82 days after NMU). The time of appearance of the first palpable cancers was shorter in rats undergoing an early pregnancy. Few cancers, however, were detected from rats after pregnancy or pregnancy and lactation was completed, and a decrease in cancer incidence from virgin rats was observed in these animals at termination of the study. Since NMU is a direct-acting carcinogen with a short half-life, no effect of pregnancy on carcinogen metabolism or binding could have occurred. Preneoplastic cells present before pregnancy appeared to have been either altered (such that their latent period was increased) or destroyed by the hormones associated with pregnancy.

Animals↗

PubMed1983

Effect of duration of high fat intake on enhancement of mammary carcinogenesis in rats.

The relationship between dietary fat and mammary carcinogenesis was studied in weanling female inbred Fischer rats fed a purified, high-fat, low-carbohydrate (HF) or a purified, low-fat, high-carbohydrate (LF) diet and given N-nitroso-N-methylurea (NMU) at 50, 90, or 133 days of age. By a change in the diet at different times after NMU treatment (50 mg/kg body wt), it was found that mammary tumor incidence was positively correlated with the time period that the rats were fed an HF diet. A dose-response effect of NMU at 10, 20, 30, 40, and 50 mg/kg body weight was also studied in groups of rats fed an HF or an LF diet. The results show an optimal carcinogenic dose of 50 mg NMU/kg body weight and a threshold dose of 27 mg NMU/kg body weight. The data conclusively demonstrated that the HF diet enhanced mammary carcinogenesis at every dose level of NMU, except 10 mg/kg. Further, the experiments also showed that an HF diet failed to promote mammary carcinogenesis in rats receiving a subthreshold dose (20 mg/kg body wt) of NMU. Altogether, the data demonstrate that an HF diet is not just a promoter but is in fact co-carcinogenic in mammary tumor induction by a chemical carcinogen.

Animals↗

PubMed1978

Tumor induction in the trachea of hamsters with N-nitroso-N-methylurea.

Experiments were conducted to study the tumor response of hamster tracheas to N-nitroso-N-methylurea. Tracheas were exposed repeatedly with the use of a tracheal catheter. Ten to 30 exposures were given over a period of 5 to 20 weeks. The carcinoma incidence (including carcinoma in situ) was 0,42, 67, 88, and 94% for 10, 15, 20, 25, and 30 twice-weekly exposures, respectively. With 10 exposures 2 of 12 hamsters developed benign tracheal tumors. Mean tumor induction time decreased when frequency of exposure was increased from 50 weeks with 10 to 15 exposures to 28 weeks with 25 to 30 exposures. The major histological types of invasive carcinomas observed were epidermoid carcinomas (54%), anaplastic large-cell and small-cell carcinomas (26%), adenocarcinomas (13%), and combined epidermoid-adenocarcinomas (7%). Sacrifice studies revealed that with 10 to 20 twice-weekly exposures only metaplastic lesions with varying degrees of cellular atypia are present at the time of the last exposure. Neoplastic lesions develop during the subsequent exposure-free interval. The data suggest that this tracheal tumor induction system may be well suited for studying problems related to development and progression of neoplastic disease.

Adenocarcinoma↗

PubMed2002

Detection of cellular responses to toxicants by dielectrophoresis.

The dielectrophoretic (DEP) crossover method has been applied to the detection of cell responses to toxicants. Time and dose responses of the human cultured leukemia (HL-60) line were measured for paraquat, styrene oxide (SO), N-nitroso-N-methylurea (NMU) and puromycin. These toxicants were chosen because of their different predominant mechanisms of action, namely membrane free radical attack, simultaneous membrane and nucleic acid attack, nucleic acid alkylation, and protein synthesis inhibition, respectively. For all treatments, the specific membrane capacitance (C(mem)) of the cells decreased while the specific membrane conductance (G(mem)) increased in dose- and time-dependent manners. The DEP responses correlated sensitively with alterations in cell surface morphology, especially folds, microvilli, and blebs, observed by scanning electron microscopy. The DEP method was more sensitive to agents that had a direct action on the membrane than to agents for which membrane alterations were secondary. The responses to paraquat and SO, which directly damaged the cell membrane, could be detected 15 min after exposure, while those for puromycin and NMU, which acted on intracellular targets, could be detected after 30 min. The detection times and dose sensitivity results showed that the DEP method is much faster and more sensitive than conventional cell and higher organism viability testing techniques. The feasibility of producing small instruments for toxicity detection and screening based on cellular dielectric responses is discussed.

Cell Membrane↗

PubMed1975

Experimental tumor induction in a circumscribed region of the hamster trachea: correlation of histology and exfoliative cytology.

A method for the induction of carcinomas in a circumscribed region of the hamster trachea is reported. By means of a special catheter, a solution of N-nitroso-N-methylurea was applied twice a week to about a 6-mm length of the trachea 10- to 16-mm distal from teh vocal cords. Slight alteration of this catheter allowed sampling of cytologic specimens directly from the surface of the carcinogen0exposed epithelium. This procedure permitted the simple and accurate correlation of sequential histologic and cytologic changes observed during tumor development in the hamsters. Noninvasive dysplastic and metaplastic lesions were seen in animals killed after 5 and 10 weeks of carcinogen application. These epithelial changes could be readily correlated with abnormal exfoliated cells abundantly present in cytologic specimens from these animals. Exposure to carcinogen for 15 weeks induced a 100% tumor incidence exclusively at the application site. More than 75% of the malignancies appeared within 15-20 weeks after the start of carcinogen administration. Most tumors were epidermoid carcinomas but some anaplastic large-cell carcinomas were also observed. Cytologic specimens of tumor-bearing animals had many cells conclusive of malignancy. The new experimental system lends itself to study of the effect of topically applied anticarcinogenic or cocarcinogenic agents on different carcinogen-induced epithelial lesions whose regression or progression can be followed by exfoliative cytology.

Animals↗

PubMed1985

Chemoprevention of N-nitroso-N-methylurea-induced mammary cancers by pretreatment with 17 beta-estradiol and progesterone.

Because hormones of pregnancy are thought to alter the mammary gland such that the epithelial cells are less susceptible to future carcinogenic insults, the present study was conducted to determine the ability of short-term treatment with 17 beta-estradiol and/or progesterone, administered immediately after puberty, to prevent mammary cancers in rats subsequently exposed to N-nitroso-N-methylurea [(NMU) CAS:684-93-5]. Beginning at 40 days of age, female outbred Sprague-Dawley rats received 20 micrograms 17 beta-estradiol and/or 4 mg progesterone for 5 weeks. NMU (50 mg/kg body wt) was administered at 96 and 103 days of age (3 and 4 wk, respectively, after the last hormone injection). Pretreatment of rats with 17 beta-estradiol plus progesterone was highly effective in preventing mammary cancer induction (88% fewer cancers compared to the cancer incidence in rats pretreated with the hormone vehicle). Wholemounts of the mammary glands of rats treated with 17 beta-estradiol plus progesterone revealed that the gland was stimulated to a highly differentiated state (similar to that observed in late pregnancy). At the time of NMU treatment, the gland had involuted but was quite different from controls; i.e. an absence of terminal end buds and terminal ducts was noted. The short-term treatment with hormones did not induce tumors and did not interfere with subsequent reproductive and lactational performance. It is apparent that stimulation of the mammary gland to a highly differentiated state early in life can provide protection against future carcinogen exposure.

Adenocarcinoma↗

PubMed1992

O6-alkylguanine-DNA-alkyltransferase activity and nitrosourea sensitivity in human cancer cell lines.

The DNA repair enzyme, O6-alkylguanine-DNA-alkyltransferase (ATase), is thought to be the principal mechanism controlling resistance to nitrosoureas and related alkylating agents. We compared the sensitivities of five human testis and five bladder tumour cell lines to two nitrosoureas (N-nitroso-N-methylurea (MNU) and mitozolomide) with cellular levels of ATase. Enzyme levels ranged from 3 to 206 fmol mg-1 protein (0.1 x 10(4) to 5.1 x 10(4) molecules/cell) in the testis lines and from 11 to 603 fmol mg-1 (0.4 x 10(4) to 9.1 x 10(4) molecules/cell) in the bladder lines. Based on IC50s in an MTT assay, the testis tumour cell lines were, on average, four times more sensitive to MNU and six times more sensitive to mitozolomide than the bladder cell lines. The cytotoxicities of MNU and mitozolomide were closely related (R = 0.9). In the testis cell lines ATase activity (molecules/cell) was related to IC50s for mitozolomide (R = 0.97) but not MNU (R = 0.78). In the bladder cell lines and overall, ATase activity correlated with cellular sensitivity to neither agent. Relatively high levels of resistance occurred in cells expressing low levels of ATase, and amongst cell lines expressing high levels of ATase, large differences in IC50s were observed. These results support the suggestion that resistance to nitrosoureas can be mediated by mechanisms other than ATase and that at relatively high levels of expression, ATase does not confer resistance in proportion to its activity.

Antineoplastic Agents↗

PubMedDate not supplied

Prolactin receptors in N-nitroso-N-methylurea-induced rat mammary tumors: relationship to tumor age and down-regulation in short-term explant culture.

Mammary tumors were induced by N-nitrosomethylurea (NMU) in young female Sprague-Dawley rats and time of appearance of the tumors was recorded daily. A total of 41 tumors of different ages (7 to 110 days old) were removed and prolactin (PRL) receptors were measured using [125I] human growth hormone (hGH) (equipotent lactogenic activity to oPRL). All but one tumor contained high PRL receptor levels. However, there was a slight decline of both free and total PRL receptor levels with increasing tumor age, with total prolactin receptor levels in tumors 7-20 days old being 32.0 +/- 1.4% compared to 26.0 +/- 2.0% in tumors 66-110 days old (p less than 0.05). In addition, for 24 of these tumors which were of sufficient size, explant cultures were carried out up to 24 h in medium-199 containing insulin and cortisol in the presence or absence of 20 microgram/ml oPRL. At this concentration, an occupation of free and a reduction of total receptor levels was observed in all explant cultures. This down-regulation also appeared to vary as a function of tumor age. Total PRL receptors declined 24.9 +/- 2.3% in young tumors (7-35 days old) compared to 41.7 +/- 4.4% in tumors 50-110 days old (p less than 0.01). The present data are important in that they demonstrate that PRL receptor levels are relatively high regardless of the age of the tumor with, however, a slight decline with increased tumor age. In contrast, the responsiveness of the tumors measured by the ability of prolactin to down-regulate its own receptors is greater in older tumors.

Animals↗

PubMed1995

FCE 27677: a novel inhibitor of acyl-CoA: cholesterol acyltransferase with potent oral hypolipidemic activity.

FCE 27677 ([(-)N-[2,6-bis(1-methylethyl)phenyl]-N'-[(4R,5R)-2- (4-dimethylaminophenyl)-4,5 dimethyl-dioxolan-2-yl]methylurea) is a new systemically available ACAT inhibitor belonging to the class of ketalic disubstituted ureas. When tested in microsomes from rabbit intestine, aorta and liver, it inhibited the enzyme with IC50 of 9.31, 6.99 and 92.2 nM, respectively. It had no effect on plasma LCAT and intestinal cytosolic cholesterol esterases and, when tested in a tissue culture system, it did not interfere with the synthesis of cholesterol, triglycerides, and phospholipids. Enzyme inhibition kinetics indicated that FCE 27677 is a non-competitive inhibitor of the enzyme with respect to acylCoA and to cholesterol. When administered mixed to a 1.5% cholesterol and 0.5% sodium cholate-enriched diet to rats, it prevented the development of hypercholesterolemia with ED50 of 0.35 mg kg-1 day-1. Given in a single oral dose to hypercholesterolemic rats it significantly reduced both the plasma lipid levels and the hepatic cholesteryl ester content within 6 h from gavage. VLDL and LDL levels and composition were also significantly affected. Similar effects were observed when the drug was given mixed to a regular chow diet for 4 weeks to hypercholesterolemic rabbits. These results are consistent with the idea that systemically available ACAT inhibitors can affect the composition and the metabolism of the atherogenic cholesteryl ester-rich VLDL and LDL. ACAT inhibitors appear promising for the correction of dyslipoproteinemias secondary to lipoprotein overproduction, and in reducing the atherogenic index of apoB-100 containing lipoproteins.

Aniline Compounds↗

PubMed2005

Induced mutation spectra at the upp locus in Salmonella typhimurium: response of the target gene in the FU assay to mechanistically different mutagens.

A novel forward mutation assay has been developed in Salmonella typhimurium based on resistance to 5-fluorouracil (FU). The mutational target in the FU assay was determined to be the uracil phosphoribosyl transferase (upp) gene. To validate the upp gene as a suitable target for monitoring a variety of induced mutations, the mutational specificity was determined for five mechanistically different mutagens. The mutagens included a polycyclic hydrocarbon (benzo[a]pyrene, B[a]P), SN1 and SN2 alkylating agents (N-nitroso-N-methylurea, MNU, and methyl methanesulfonate, MMS, respectively), a frameshift mutagen (ICR-191), and an oxidative-damaging agent (hydrogen peroxide, H2O2). Induced mutation frequencies were measured in the presence and absence of the plasmid pKM101 (strain FU100 and FU1535, respectively). pKM101 renders FU100 more susceptible to induced mutation by providing error-prone replicative bypass of DNA adducts. B[a]P, MMS, and H2O2 failed to induce the mutant frequency in FU1535, demonstrating the dependence of pKM101 on induced mutations with these agents. ICR-191 and MNU were not dependent on pKM101, and did significantly induce mutations in FU1535. In contrast to FU1535, all agents significantly induced mutations in FU100. Approximately 60 independent mutants were sequenced for each agent that significantly induced the mutant frequency above background. The resulting mutational spectra illustrated predictable molecular fingerprints based on known mutagenic mechanisms for each agent. The predominant mutations observed were G:C to T:A transversions for B[a]P, A:T to T:A and G:C to T:A transversions for MMS, G:C to T:A transversions and A:T frameshifts for H2O2, G:C frameshifts for ICR-191, and G:C to A:T transitions for MNU. It can be concluded that the upp gene in the FU assay is a sensitive and suitable target to monitor a variety of induced mutations in Salmonella.

Aminacrine↗

PubMed1996

Correction of dyslipoproteinaemia of casein-fed rabbit by FCE 27677, a potent novel ACAT inhibitor.

Rabbits fed a wheat starch casein diet develop hypercholesterolaemia characterized by the plasma elevation of low density lipoprotein (LDL) that is caused by oversecretion of apoB-100 containing lipoproteins by the liver and by the suppression of the EDTA-sensitive hepatic beta- very low density lipoprotein (VLDL)-LDL receptor. In this study, the effect of FCE 27677 ((-)N-[2,6-bis(1-methylethyl)phenyl]-N'-[(4R,5R)-2-(4-dimethylaminoph eny l)-4,5-dimethyl-dioxolan-2-yl]methylurea) a novel potent systemic acylCoA:cholesterol acetyltransferase (ACAT, EC 2.3.1.26) inhibitor, has been evaluated. When New Zealand White rabbits were fed with casein for 4 weeks, LDL cholesterol increased from 14 +/- 3 mg/dl-1 to 77 +/- 6 mg/dl-1. By contrast the animals receiving FCE 27677 (10 mg kg-1 d-1) mixed with the casein diet maintained a normal LDL concentration (22 +/- 3 mg dl-1). This hypolipidaemic effect was also observed when rabbits previously made hypercholesterolaemic by being fed casein for 4 weeks were then treated for a month with FCE 27677. [125I]LDL plasma turnover studies and [125I]LDL binding studies to liver membranes were carried out with the purpose of investigating the mechanism of action of the drug. The LDL apoB-100 production rate in chow-fed, casein-fed, and casein-fed rabbits receiving FCE 27677, was respectively 10.5, 22.4, and 12.5 mg kg-1 d-1. The turnover rate of [125I]LDL in the animals receiving the drug was not, however, different from that in the rabbits fed the casein diet alone (2.381 vs 2.079 pools d-1). Both values were lower than that in chow-fed animals (3.271 pools d-1). FCE 27677 did not normalize the activity of the hepatic beta-VLDL-LDL EDTA-sensitive receptor which is suppressed by casein feeding. Altogether the results are consistent with the idea that FCE 27677 by acting through inhibition of the cholesterol esterification in the liver normalizes the LDL synthetic rate. ACAT inhibitors may be useful drugs for the treatment of human dyslipoproteinaemia secondary to derangement of the apoB-100 synthetic rate.

Aniline Compounds↗

PubMed1976

The roles of age at treatment and dose in carcinogenesis in C3Hf/Dp mice with a single administration of N-nitroso-N-methylurea.

C3Hf/Dp mice were given a single i.p. injection of 50, 25 or 5 mug/g N-Nitroso-N-Methylurea (NMU) at either 1 or 70 days of age or 50 mug/g at 21 days of age. They were observed until death or until 120 weeks of age. The two highest doses of NMU produced tumours in a wide spectrum of organs, including the thymus, forestomach, lung, liver (only in males), kidneys, ovaries and orbital glands. The only two tumour types which appeared to be closely related to the occurrence of death were thymic lymphomata (most of which were found in mice dying before 40 weeks after treatment) and carcinomata of the forestomach. Lifetime analyses are presented concerning the occurrence of these two tumour types as well as the occurrence of any tumour after 40 weeks of age or since treatment. Incidences of thymic lymphomata were 67.6%, 39.0% and 21.2% in mice receiving 50 mug/g NMU at 1, 21 and 70 days respectively and 17.1% in mice receiving 25 mug/g at 1 day. In the other groups the incidence of thymic lymphomata was zero or negligible. The rate of progression of thymic lymphomata until death was related to both earliness of treatment and dose. On the contrary, incidences and progression of carcinomata of the forestomach were unrelated to age at treatment. Since breakdown of NMU is very rapid and does not require enzymes, these results are considered as evidence that host-tumour interaction differs from organ to organ. No excess of tumours over the controls was found in mice receiving 5 mug/g either at 1 or 70 days of age.

Age Factors↗

PubMed1982

Effects of isoproterenol on mammary gland tumors induced by N-nitroso-N-methylurea and salivary gland tumors induced by 7,12-dimethylbenz[a]anthracene.

The effect of isoproterenol (IPR) (20 mg/kg, twice per wk) on mammary gland tumors induced by N-nitroso-N-methylurea (NMU) (40 or 77 mg/kg, iv) was studied. Within 18 weeks 50--60% of the noninbred female Sprague-Dawley rats that received a single injection of NMU developed carcinomas of the mammary gland. In addition, a malignant lymphoma was observed. There was no change in the incidence of tumors if NMU was administered at the time that DNA synthesis was stimulated in the submandibular glands by two injections of IPR (160 mg/kg, ip) given 24 hours apart. Tumors of unequivocal salivary gland origin were not observed, irrespective of whether NMU was given at the peak of stimulated DNA synthesis or without pretreatment with IPR. However, in 10% of the tumor-bearing rats, tumors were found in the neck region. These tumors could be separated from the salivary glands by dissection and were of mammary gland origin. Chronic treatment with IPR caused marked enlargements of the parotid and submandibular glands with hypertrophy of the acinar cells and degeneration of the duct system. Such a treatment caused a high death rate but no change in the incidence of the tumors. The effect of chronic IPR treatment (10 mg/kg twice per wk or 5 mg/kg three times per wk) on submandibular gland tumors induced by 7,12-dimethylbenz[a]anthracene (DMBA) was also studied. With the intraglandular injection of 100 or 200 micrograms of DMBA, the incidences of squamous cell carcinomas in the glands were 6.8 and 38.6%, respectively. Chronic administration of IPR after the instillation of DMBA caused a high death rate but no statistically significant change in the incidence of salivary gland tumors.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed2000

Investigation on the possible formation of N-nitroso-N-methylurea by nitrosation of creatinine in model systems and in cured meats at gastric pH.

N-Nitroso-N-methylurea (NMU) is a highly potent direct-acting carcinogen that has been shown to induce cancer in a number of animal species. Although previous research has indicated that nitrosation of creatinine (CRN), a common constituent of meats, dried fish, and seafoods, can form traces of NMU, there is uncertainty as to (1) the yield of NMU and (2) whether detectable amounts of NMU can be formed from cured meats following nitrosation under acidic conditions given the low residual levels of nitrite found in cured meats at the present time. Lack of sensitive and specific analytical methods most likely has hindered progress in research in these areas. An HPLC postcolumn denitrosation-thermal energy analyzer technique and a GC-MS confirmation technique were developed for the determination of NMU in cured meats. Both techniques are highly sensitive (0.5 and 0.03 ppb, respectively) and specific. The optimum pH for NMU formation from CRN ranged between pH 1 and pH 3, and the yields of NMU under variable reactant concentrations ranged between 0.00004 and 0.0046%. When 27 samples of various cured meats (10 g aliquots each) were acidified with HCl (final pH values of 0.8-2.5) and incubated at room temperature for 2 h, without any additional nitrite, 24 gave results below detectable levels but 3 formed 2-26 ng of NMU/10 g of meat. Incubation of the negative meats with additional nitrite (50-500 microg/g of meat) formed 0.6-176 ng of NMU/10 g of sample. Although the amounts of NMU formed were extremely small, this seems to be the first reported formation of NMU from cured meats with and without additional nitrite.

Creatinine↗

PubMed1983

Carcinogenicity of single doses of N-nitroso-N-methylurea and N-nitroso-N-ethylurea in Syrian golden hamsters and the persistence of alkylated purines in the DNA of various tissues.

The carcinogenicity of N-nitroso-N-methylurea (NMU) and N-nitroso-N-ethylurea (NEU) has been determined in adult male Syrian golden hamsters following a single i.p. injection or two-thirds of the acute 50% lethal dose, or 30 and 60 mg/kg, respectively. The principal site of action of these agents was the forestomach, squamous cell papillomas of this organ developing in 53 and 61% of the animals receiving the higher doses of NMU and N-nitroso-N-ethylurea, respectively. NMU also induced a low incidence of liver tumors (17%). Very few tumors were seen at other sites. The formation and removal of alkylated purines in DNA was measured in various tissues up to 50 hr after administration of [14C]NMU. Methylation products were detected in all tissues examined, the level in liver being somewhat higher than in other tissues. The removal of 7-methylguanine and 3-methyladenine from DNA occurred at approximately similar rates in all tissues examined, indicating no substantial differences in N-glycosylase activities. Removal of the promutagenic DNA lesion O6-methylguanine varied considerably from tissue to tissue; very little occurred in brain or kidney, while up to 36 and 32% were lost from DNA of intestine and testes, respectively. In the liver, there were relatively small changes in O6-methylguanine levels up to 24 hr; but by 50 hr, 38% had been removed. The persistence of O6-methylguanine relative to 7-methylguanine was highest in the DNA of the brain and intestine and lowest in that of the liver. These results indicate that in this experimental system, the formation and persistence of O6-methylguanine in DNA is insufficient alone to account for the organotropic effect of NMU.

Alkylation↗

PubMed1981

Influence of the estrous cycle during carcinogen exposure on nitrosomethylurea-induced rat mammary carcinoma.

The influence of individual stages of the rat estrous cycle during exposure to I-nitroso-I-methylurea (NMU) on mammary tumor incidence, latency, number, and cytosol receptor dynamics for estrogen and progesterone was determined. Virgin female Buffalo rats were separated into three groups on Day 53 according to their vaginal smear pattern. NMU (5 mg/100 g body weight, i.v.) was administered in three monthly doses beginning at 53 to 55 days of age on diestrus, proestrus, or estrus between 9:00 and 11:00 a.m. Groups of rats had their second and third injections of NMU on the same day of the estrous cycle as their initial injection. All animals were killed during the morning on a diestrus day. Receptors for estrogen and progesterone were determined by a modified dextran-coated charcoal method and by sucrose density gradient analysis. Mean latencies to first tumor appearance in diestrus, proestrus, and estrus groups were 104.4, 83.6, and 91.4 days, respectively (p less than 0.05, diestrus versus estrus and proestrus) following the first NMU injection. The mean number of tumors per rat was significantly higher in rats injected on proestrus (4.5) or estrus (4.3) than on diestrus (2.0). Estradiol bound to receptor sedimented at 8 and 4 s and was suppressed by diethylstilbestrol and estradiol. Progesterone receptor migrated to 7.8 and 4 s regions. Estrogen receptor incidence (100%) and content (16.7 fmol/mg cytosol protein) was highest in rats injected on diestrus. In the proestrus and estrus injected groups, estrogen receptor incidence was 95 and 63% and content was 10.2 and 11.2 fmol/mg protein, respectively. The affinity of estradiol for its receptor was not significantly altered in any group. Although there were no statistically significant difference in progesterone receptor incidence or affinity between groups, progesterone receptor content (74.6 fmol/mg cytosol protein) was significantly higher in tumors from rats injected on proestrus than on diestrus. These data suggest that the prevailing hormonal milieu of the estrous cycle during NMU exposure may be critically important to the subsequent biological behavior and steroid receptor status of carcinogen-induced rat mammary tumors.

Adenocarcinoma↗

PubMed1992

A possible explanation for the differential cancer incidence in the intestine, based on distribution of the cytotoxic effects of carcinogens in the murine large bowel.

The ability of four mutagenic/carcinogenic chemicals administered as single doses to induce a programmed form of cell death (apoptosis) in the BDF1 mouse large bowel was studied and compared with a previous study on the small intestine using the same mice. The number of apoptotic cells was counted following treatment with the direct-acting agents N-nitroso-N-methylurea (NMU) and N-nitroso-N-ethylurea (NEU) and two agents which require metabolic activation 1,2-dimethylhydrazine (DMH) and N-nitrosodimethylamine (NDMA). DMH (80 mg/kg) was the most effective at inducing acute cell death and this was closely followed by NMU (200 mg/kg). The least effective agent in the large bowel was NDMA. The peak yield of apoptosis occurred between 4 h (NEU) and 8 h (DMH) after treatment. An analysis of the changing shapes of the frequency plots of apoptosis at each cell position in the crypt at various times after exposure permits an estimate to be made of the position in the crypt of the primary target cells for the cytotoxic action at time t = 0. For the agents studied, this is in the range of the 5th to the 10th position from the base of the crypt. This distribution for the target cells for apoptotic cell death is not coincident with that for the presumptive stem cells, which is at cell position 1 or 2. Comparisons with results previously obtained in the small intestine (ileum) of the same mice show that the relative cytotoxic effectiveness of the four agents differs. Furthermore, the position of the target cells is at about the 4th position from the bottom of the crypt in the ileum, and here the distribution is coincident with that presumed for the stem cells. Our interpretation of the data is that damaged cells in the stem cell region of the small bowel are removed by the activation of a cell suicide programme, which effectively removes potentially harmful genetic alterations. In contrast, in the large bowel, cell death is not initiated particularly strongly in the stem cell region but tends to occur higher in the crypt. The absence of this selective deletion process may result in the perpetuation of deleterious mutations in the colonic stem cell population and this may explain in part, the higher incidence of cancers observed in the large bowel.

1,2-Dimethylhydrazine↗