Showing papers on "7,12-Dimethylbenz[a]anthracene published in 1967"

The Interaction of 7,12-Dimethylbenz(a)anthracene with Cells Sensitive and Resistant to Toxicity Induced by This Carcinogen

Abstract: The multiplication of monolayer cultures of transformed rodent cells and normal or transformed human cells was not inhibited by concentrations of 7,12-dimethylbenz(a)anthracene (DMBA) 200–500 times greater than those that inhibited the multiplication of normal embryonic rodent cells. Fluorescence microscopy showed that DMBA localized to about the same degree within the cytoplasm of cells that were sensitive or resistant to the toxic effect of the carcinogen. Autoradiography with DMBA-3H and an aqueous cell fixative (formalin) revealed that the carcinogen was distributed throughout the cytoplasm and nucleus and that the concentrations were similar in sensitive and resistant cells. However, when the cells were treated with a fixative in which DMBA is soluble (Carnoy's), most (90%) of the labeled compound was eliminated from the resistant cells whereas a considerable amount appeared to be bound within both the cytoplasm and the nucleus of sensitive cells. The difference in the binding of DMBA by the 2 types of cells was confirmed by isolating and assaying for radioactivity individual cellular constituents after cells had been exposed to DMBA-3H. Sensitive cells bound 10–50 times more DMBA to their nucleic acids and protein than did resistant cells. With mouse embryo cells, the amount of DMBA bound to DNA and protein was proportional to the growth-inhibitory effect of the carcinogen within the dose range 0.01–0.1 µg/ml.

Enhancement of lung adenoma formation by neonatal thymectomy in mice treated with 7,12-dimethylbenz(a)anthracene or urethan.

Abstract: The influence of neonatal thymectomy on lung adenoma formation in mice was investigated. SWR and Swiss mice thymectomized at 3 days of age and given a single dose of 7,12-dimethylbenz (a) anthracene (DMBA) or urethan showed significantly higher incidences of tumors than did intact controls, when examined at various intervals after the carcinogenic treatment. These differences in the yield of tumors were manifested as early as 10 weeks after urethan administration. Levels of hemolysins and hemagglutinins in response to sheep erythrocytes were decreased in thymectomized mice as compared with normal animals. The probable relationship between enhanced susceptibility to chemical carcinogens and immunological deficit of neonatally thymectomized mice is discussed.

Chromosome Abnormality in Rat Leukemia Induced by 7,12-Dimethylbenz[a]anthracene

Abstract: A high percentage of consistent chromosome abnormality, trisomy of the longest telocentric chromosome, was found in leukemias induced in rats of the Long-Evans strain by pulse doses of 7,12-dimethylbenz[a]anthracene. Cells with this abnormality were large, immature, and mononuclear and tended toward erythroblastic maturation.

The effect of pretreatment with adrenal-protecting compounds on the metabolism of 7,12-dimethylbenz[a]anthracene and related compounds by rat-liver homogenates

Abstract: 1. 7,12-Dimethylbenz[a]anthracene is converted by rat-liver homogenates into products with the properties of the 7- and 12-hydroxymethyl derivatives, the 7,12-dihydroxymethyl derivative, the related carboxylic acids and ring-hydroxylated products such as the 8,9-dihydro-8,9-dihydroxy derivative and phenols. Ring-hydroxylated products and products arising from the further oxidation of the hydroxymethyl groups were formed when the hydroxymethyl derivatives were themselves incubated with rat-liver homogenates. 2. Pretreatment of the animal with 3-methylcholanthrene or with Sudan III, which can protect rat adrenal glands from damage by 7,12-dimethylbenz[a]anthracene or by its 7-hydroxymethyl derivative, led to an increased rate of metabolism of 7,12-dimethylbenz[a]anthracene and its hydroxymethyl derivatives. The metabolic routes mainly affected were those involving the formation of ring-hydroxylated products. 3. Pretreatment with phenobarbitone led to a small increase in the rate of metabolism of the hydrocarbon and of its hydroxymethyl derivatives, but the increase appeared mainly to involve increased metabolism of the methyl and hydroxymethyl groups. 4. Pretreatment with metyrapone increased the rate of metabolism of the hydrocarbon mainly by increasing the amounts of products resulting from hydroxylation of the methyl groups: small increases in the amounts of ring-hydroxylated products were also produced. 8. Of a number of hydrocarbons and of derivatives of 3-methylcholanthrene tested as enzyme inducers, 3-methylcholanthrene itself was the most effective.

Hormones influencing postpartum growth of 7,12-dimethylbenz(a)anthracene-induced rat mammary tumors.

Abstract: Summary The endocrine factors affecting postpartum growth of mammary tumors were studied in Sprague-Dawley female rats bearing 7,12-dimethylbenz(a)anthracene-induced mammary tumors. The majority of tumors were classified as mammary adenocarcinomas, but a few mammary fibroadenomas and “mixed” tumors were also observed. All rats developed tumors during pregnancy and all tumors grew rapidly until parturition. Ovariectomy performed on Day 2 of lactation abolished the stimulatory effect of suckling on tumor growth in rats nursing 6 pups. While the daily administration of 1 mg progesterone/day to ovariectomized lactators resulted in growth of only a few tumors, daily administration of 6 mg progesterone stimulated growth of nearly 50% of the tumors during the postpartum period. Administration of either bovine or ovine prolactin to non-nursed, tumor-bearing rats for 25 days postpartum stimulated tumor maintenance and growth to varying degrees, depending upon the dose. The stimulatory action of prolactin on tumor growth was abolished by ovariectomy performed on Day 2 postpartum. Tumor growth was dependent on the continuance of the hormone treatment, as most growing tumors regressed after cessation of hormone treatment. These data indicate that ovarian progesterone, acting either directly or in synergism with prolactin, is necessary for the growth of chemically-induced mammary tumors during lactation.

Variations dependent on age and diet in the metabolism of 7,12-dimethylbenz[a]-anthracene by rat liver homogenates.

Abstract: 7,12-DIMETHYLBENZ[A]ANTHRACENE (DMBA) causes severe adrenocortical necrosis when administered intragastrically to 50 day old rats1, but it has no effect on the adrenal glands of 25 day old animals2. The activity of the hydrocarbon seems to depend on the formation of an active metabolite, probably 7-hydroxymethyl-12-methylbenz[a]anthracene (7-OHM-12-MBA)3,4; the isomeric 12-hydroxymethyl-7-methylbenz[a]anthracene (12-OHM-7-MBA) is a metabolic product of DMBA but has no effect on the adrenal3. Damage to the adrenal can be prevented by pretreating animals with compounds that enhance hepatic detoxicating enzymes5,6, apparently by increasing the yields of inactive ring-hydroxylated products, such as 8,9-dihydro-8,9-dihydroxy-7,12-dimethylbenz[a]anthracene, at the expense of those hydroxylated on the methyl groups and also by inactivating 7-OHM-12-MBA itself by ring hydroxylation, to yield products such as 8,9-dihydro-8,9-dihydroxy-7-hydroxymethyl-12-methylbenz[a]anthracene7. Treatments which reduce hepatic detoxicating enzymes also prevent DMBA-induced adrenal necrosis8, probably by reducing the overall metabolism of the hydrocarbon. It seemed possible that the differing susceptibilities to DMBA-induced adrenal necrosis of the 25 and 50 day old rats developed because animals of the two age groups have different activities of hepatic enzymes, and so we have investigated the in vitro metabolism of DMBA by liver homogenates prepared from rats of different ages.

Experimental induction of ovarian tumors in mice treated with single administration of 7,12-dimethylbenz[a]anthracene, and its histopathological observation.

Abstract: 1) Induction of ovarian tumor with a single intragastric instillation of a large but tolerable doses of 7,12-dimethylbenz[a]anthracene (DMBA) was investigated on young female mice of C3H and C57BL strains, rats of Sprague-Dawley strain, guinea pigs, and rabbits. The ovarian tumor occurred in a high incidence only in C3H mice. 2) The induction of ovarian tumor in C3H mice with DMBA by various routes of administration such as intragastric instillation, intraperitoneal or intravenous injection was studied. The following tumor incidences were obtained in the treated mice: Single feeding, 59% until 7th month; intraperitoneal injection, 36% until 4th month; single intravenous injection, variable percentages at each month and average 57% after 6 months. Intraperitoneal injection of DMBA induced ovarian tumor earlier and in higher incidence than by other two routes but mortality of mice was unfortunately very high. 3) Histological observations revealed no normal ovaries in C3H mice given DMBA intravenously. Follicular structures were destroyed and oocytes vanished within one month. Proliferation of granulosa cell following its earlier non-specific pathological change progressed from microscopical nodule to a sizable gross tumor. These tumors were all granulosa-celled type. 4) Granulosa cell tumor arose probably from surviving granulosa cells in the partially degenerated follicles and its growth was stimulated by pituitary gland but there was still a probability that granulosa cell tumor might have originated from theca cells. 5) Frequent study of vaginal smears demonstrated possible association between the presence of tumor and estrogen activity.

Development of adrenal cortical carcinoma in C3H mice following castration and the administration of 7,12-dimethylbenz(a)anthracene.

Abstract: SPONTANEOUS carcinomas of the adrenal cortex appear to be extremely rare in mice. Slye, Holmes and Wells (1921) found only 4 such tumours in 33,000 autopsies on mice. However, mice of the CE (extreme dilution) strain respond to gonadectomy by developing nodular hyperplasia of the adrenals, followed by adrenal cortical carcinoma in all animals after 6 months (Woolley and Little, 1945a and b). Some strains show little or no adrenal response to gonadectomy, but others (which include DBA and C3H) show an intermediate response (Woolley, Fekete and Little, 1940). In the latter animals, groups of large, vacuolated, lipid-laden cells taking up very little eosin begin to appear in the cortex and such areas of \" type B \" cells can eventually be observed as white spots on the surface of the adrenal. Later they may become filled with yellow-brown pigment. When these areas have increased until the capsule of the adrenal is raised, the condition is known as nodular hyperplasia. There is secretion of sex hormones, which will cause vaginal cornification and will support the development of mam-mary tumours. Nodular hyperplasia also occurs in intact C3H females towards the end of the second year of life (Pilgrim, 1957). The adrenal hyperplasia in these strains is believed to be a response to increased gonadotrophin which results when the pituitary is released from inhibition by sex hormones following gonadectomy (Hummell, 1954), for it can be prevented by administration of oestrogens or androgens, or by hypophysectomy. It can also be produced in intact mice by uniting them in parabiosis with spayed partners, so that increased gonadotrophin produced by the spayed partner crosses to the also showed that progression of adrenal hyperplasia to carcinoma in CE mice can be prevented by ovarian isografts. Ovarian tumours in mice are also believed to result from a similar disturbance of the mechanisms whereby the gonadotrophin secretions of the pituitary control the secretion of ovarian steroids, which in turn feed back to regulate the secretion of the pituitary. They can be induced in ovaries transplanted to the spleen of a castrated animal, which results in destruction of ovarian steroids by the liver (Biskind and Biskind, 1944), or when the ovary has been damaged by X-rays (Furth and Furth, 1936), or by the administration of triethylene melamine or myleran (Conklin, Upton and Christenberry, 1965), or by 7,12-dimethylbenz(a)an-thracene (Howell, Marchant and Orr, 1954). It has been shown for most of …

Hormonal Treatment of Mammary Tumors in Rats Induced by 3-Methylcholanthrene (NSC-21970) and 7,12-Dimethylbenz(a)Anthracene (NSC-408823)

Abstract: Mammary tumors induced in female rats by repeated gastric instillations of 3-methylcholanthrene grow more rapidly than tumors induced by single gastric instillations of 7,12-dimethylbenz ( a ) anthracene. Over a 6-week period, the inhibition of tumor growth by ovariectomy or by estradiol benzoate is more evident by inhibition of tumor weight of the MCA tumors, but complete regressions occur more frequently with DMBA tumors. Mammary tumors appearing in female rats after administration of carcinogenic polycyclic hydrocarbons are used for the evaluation of cancer chemotherapeutic agents. The tumors are partially hormonedependent and in other ways are considered to resemble mammary carcinoma in humans. Two experimental systems have been most popular. The 1st uses female Wistar rats that receive repeated gastric instillations of 3-methylcholanthrene (MCA), a method introduced by Shay and his coworkers (8) in 1949. The 2d system uses female Sprague-Dawley rats that are given single doses of 7,12-dimethylbenz( a )anthracene (DMBA), the method introduced by Huggins et al. (7) in 1961. Few studies have compared systematically the appearance and behavior of mammary tumors induced by these 2 methods. We have reported one such study (6), and showed that the Sprague-Dawley rat is more susceptible than the Wistar rat to the induction of mammary tumors after gastric instillations of both carcinogens, as expressed in a greater proportion of animals that develop tumors, shorter mean time of appearance of such tumors, and a greater number of tumors per rat. These data are summarized in Table 1. The same study (6) also revealed that the mammary tumors induced by repeated administrations of MCA grew significantly more rapidly than the tumors induced by single doses of DMBA, as expressed by the mean diameter of the masses on Day 30. There was no difference in growth in the 2 strains of rats. These data, recalculated as the mean volume of tumor per rat 21 days after appearance, are given in Table 2. Tumors induced by multiple administrations of MCA in Wistar rats have been used in this laboratory in a series of studies that tested over 100 hormonal and nonhormonal chemicals (1,2,4,5). Tumors induced by single doses of DMBA in Sprague-Dawley rats have been used in similar investigations by Griswold et al. (3) and Teller et al. (9). We (4) suggested that the difference in the growth rate, as well as the difference in the effect of MCA and DMBA on the hormonal status of the host, could affect the therapeutic response (4). A direct comparison of the response of MCA- and DMBA-induced tumors to several chemotherapeutic agents appeared desirable, and such an experiment was started. This report compares the growth of mammary tumors in female Wistar and Sprague-Dawley rats that received MCA or DMBA, and the response of such tumors to ovariectomy, estradiol benzoate (NSC-9566) and dromostanolone propionate (NSC-12198).[3][1] [1]: #fn-3

Effect of nursing and litter size on growth of 7,12-dimethylbenz(a)anthracene (DMBA)-induced rat mammary tumors.

Abstract: Effect of nursing and litter size on growth of 7,12-dimethylbenz(a)anthracene (DMBA)-induced rat mammary tumors.

Carcinogenesis in rabbits injected at birth with 7,12-dimethylbenz(a)anthracene.

Abstract: ImagesFigs. 4-6Figs. 1-3

Toxicity of intraperitoneal injections of 7, 12-dimethylbenz[a]anthracene in inbred mice.

Abstract: Summary The sensitivity of A/HeJ, AKR/J, C3H/HeJ, C57BL/6J, C58/J, and DBA/2J male mice to single i.p. injections of 7, 12-dimethylbenz[a]anthracene (DMBA) was investigated. The drug was administered in a single dose of 0.75 to 3 mg per mouse and animals were sacrificed 5–20 days after injection. The AKR mice were least affected by DMBA. Acute peritoneal inflammation accompanied by accumulation of an exudate was pronounced in the C57BL/6, A/He, C58, C3H/He mice and only slight in DBA/2 and AKR mice. Depression of the lymphocyte count in the peripheral blood and decrease of the weight of spleen and thymus were also more pronounced in strains with increased mortality rates and severe peritoneal inflammation. Toxicity remained the same whether sesame oil, dimethyl sulfoxide, or hexadecane were the solvents, but decreased when DMBA was suspended in physiologic saline containing Tween 80. Male and female AKR and C57BL/6 mice responded the same to treatment.

The effect of liver interference on mammary tumour induction by 7,12-dimethylbenz(a)anthracene in Sprague-Dawley rats.

Abstract: The effect of liver interference on mammary tumour induction by 7,12-dimethylbenz(a)anthracene in Sprague-Dawley rats.