Showing papers on "7,12-Dimethylbenz[a]anthracene published in 1968"

Inhibition of the Carcinogenic Action of 7,12-Dimethylbenz(a)anthracene by Beta-Naphthoflavone∗:

Abstract: SummaryBeta-naphthoflavone, a potent inducer of increased polycyclic hydrocarbon hydroxylase activity, was found to inhibit the occurrence of neoplastic lesions resulting from DMBA in experiments in which the beta naphthoflavone was given prior to the carcinogen. Pulmonary adenoma formation in the A/HeJ strain mouse resulting from oral administration of DMBA and mammary tumor formation in the Sprague-Dawley rat also from oral administration of the same carcinogen were both inhibited by beta-naphthoflavone.

The metabolism of 7,12‐dimethylbenz(A)anthracene in cell cultures

Abstract: When tritiated 7,12-dimethylbenz (a)anthracene (DMBA) was incubated in the presence of monolayer cultures of normal embryonic rodent cells, a large fraction of the carcinogen was metabolized to water-soluble derivatives that could be recovered from the medium. Small amounts of material with chromatographic properties similar to those of the monohydroxymethyl derivatives of DMBA also were recovered from the medium, but no compound resembling the dihydroxymethyl derivative was detected. In the presence of a transformed line of hamster embryo cells and a strain of human diploid cells, DMBA was metabolized to the hydroxymethyl and water-soluble derivatives to a much lesser extent. The amount of carcinogen metabolized by HeLa cells was intermediate between those of the normal and of the transformed rodent cells, but the main water-soluble derivatives produced in the presence of rodent cells and HeLa cells were different. Thus, DMBA was metabolized to water-soluble derivatives primarily by those cells which are sensitive to cytotoxicity induced by the carcinogen, i.e., the normal rodent cells and HeLa cells; the transformed hamster cells and the normal human cells are relatively resistant to the carcinogen-induced cytotoxicity. The conversion of DMBA to water-soluble metabolites was inhibited by actinomycin D. The hydroxymethyl derivatives of DMBA were taken up by the normal rodent cells, but were approximately 100 times less cytotoxic than DMBA. The main water-soluble derivative formed in the presence of rodent cells was partially purified and added to fresh cell cultures; it was found that this derivative is taken up by cells at a much slower rate than the original compound.

Effects of Multiple Pituitary Homografts or Progesterone on 7,12-Dimethylbenz[a]anthracene-lnduced Mammary Tumors in Rats

Abstract: This investigation evaluates the effects of prolactin-secreting pituitary homografts and progesterone on the induction of mamary tumors in female rats subsequently treated with 712-dimethylbenz[alpha]anthracene (DMBA). Immature female Sprague-Dawley rats were divided into 5 groups: group 1 intact controls; group 2 ovariectomized; group 3 intact and 4 pituitary homografts; group 4 ovariectomized and 4 pituitary homografts; and group 5 intact and given injection of 4 mg progesterone daily. Pituitary transplantation and/or ovariectomy were performed at age 25 days. Progesterone was injected beginning at 30 days of age and continued for 40 consecutive days. At age 55 days all animals were given a single intravenous dose of 5 mg DMBA. At the end of the study the percent of tumor incidence average number of tumors/rat and average total weight of tumors/rat (g) were: group 1 100% 12.2 +or- 1.2 16.2 +or- 3.5; group 2 0; group 3 73% 4.7 +or- 1.3 5.4 +or- 2.0; group 4 0; and group 5 79% 3.3 +or- 0.7 5.9 +or- 4.6. Percentage of rats with tumors average number of tumors/rat and average total weight of tumors/rat were significantly decreased in intact rats bearing 4 pituitary homografts and in intact rats given injections of progesterone as compared to the intact controls. The inhibitory effect of the prolactin-secreting pituitary homografts appears to be mediated at least in part through the ovary since daily injections of progesterone resulted in a comparable inhibition of mammary tumorigenesis. These data indicate that prolactin and/or progesterone by stimulating growth and development growth of the mammary gland inhibit DMBA-induced mammary tumorigenesis if given sufficiently prior to carcinogen treatment. (authors)

Enhancement and inhibition of the induction by 7,12-dimethylbenz(a)anthracene of mammary tumours in female Sprague-Dawley rats.

Abstract: ImagesFig. 6-9

Inhibition by Actinomycin D of DNA Synthesis and Skin Tumorigenesis Induced by 7,12-Dimethylbenz(a)anthracene

Abstract: The effect of a wide dose-range of actinomycin D on initiation of skin tumors by 7,12-dimethylbenz(a)anthracene (DMBA) and on DNA synthesis in skin was studied. Fifty to ninety micrograms caused a 76–92% inhibition of skin tumorigenesis. Twenty to forty micrograms caused a 26–79% inhibition. Fifteen micrograms of actinomycin D resulted in a 31–63% inhibition in 3 experiments but no inhibition in 2 other experiments. No inhibition of skin tumorigenesis was observed with 1, 5, or 7.5 μg. The effect of 3–60 μg actinomycin D on DNA synthesis in skin was determined by incorporation of thymidine-3H into DNA. DNA synthesis was inhibited by 24–60 μg of actinomycin. Inhibition began 1–2 days after treatment and lasted up to 4 days. DNA synthesis was stimulated subsequent to inhibition. Twelve micrograms inhibited DNA synthesis in one experiment but not in another, and the inhibition lasted only one day; no inhibition was observed with 3 μg. The inhibition of thymidine-3H incorporation by actinomycin D was not due to altered precursor pool size, since the dilution of prelabeled DNA by normal DNA synthesis was prevented by actinomycin D. Treatment with 16 μg DMBA did not significantly alter the effect on DNA synthesis of varying doses of actinomycin D. By itself, 16 μg DMBA caused a slight inhibition of DNA synthesis on the day of treatment, but this recovered by the following day; inhibition by 200 μg DMBA lasted an additional day. Thus, tumorigenesis and DNA synthesis are inhibited by comparable doses of actinomycin D. This suggests that initiation of skin tumorigenesis requires the synthesis of DNA or a process associated with cell replication.

Inhibition by actinomycin D of DNA and RNA synthesis and of skin carcinogenesis initiated by 7,12-dimethylbenz[a]anthracene or beta-propiolactone.

Abstract: Summary Application of 84 µg of actinomycin D inhibits skin tumor formation initiated by either 7,12-dimethylbenz[ a ]anthracene (DMBA) or β-propiolactone (BPL). Treatment with this dose of actinomycin D inhibits the binding of DMBA to skin DNA by 40%, but does not affect BPL binding to DNA. Inhibition of binding of initiators to DNA cannot explain more than a small part of the inhibition of tumor formation by actinomycin D. A dose of 10 µg of actinomycin D inhibits tumor formation by 40–50% when given the same day as the initiator (DMBA or BPL) or 1 or 7 days later. Application of this dose of actinomycin D inhibited RNA synthesis only slightly for about 12 hours (6–18 hours after treatment), but inhibited DNA synthesis by 75–90% for at least 2 days (from 24–72 hours after treatment). The inhibition of tumor formation by actinomycin D may be related to its inhibition of the incorporation of thymidine- 3 H into skin DNA. It is not known whether this block of DNA synthesis is reversible or irreversible in potential tumor cells.

Reversible inhibition of DNA synthesis in hamster embryo cells in culture: action of 1,2-benzanthracene and 7,12-dimethylbenz(a)anthracene.

Abstract: The effects of the relatively weak carcinogen, 1,2-benzanthracene (BA), and its potent carcinogenic derivative, 7,12-dimethylbenz(a)anthracene (DMBA), on the resumption of DNA synthesis in Syrian hamster embryo cells blocked in the S phase of the mitotic cycle, were analyzed. A maximum level of binding of BA to DNA (1.08 molecule/200,000 nucleotide units) occurred after 4 hours of treatment of cells which had been released from thymidine blockage with 10-4 m deoxycytidine. The binding of this level of BA appeared to have little if any effect on the movement of cells from the DNA replicative phase into mitosis. In contrast, DMBA produced an immediate suppression in the rate of DNA synthesis, which is normally resumed within minutes after release under control conditions or BA treatment. Furthermore, DMBA reduced the mitotic activity by 50% at 4 hours and the maximal level of binding to DNA (0.7 molecule/200,000 nucleotide units) occurred only after 24 hours of treatment. It was shown that BA exerted a protective action against the suppressive activity of DMBA on DNA synthesis and the movement of cells into mitosis. The binding of DMBA-3H to DNA was almost abolished (97% at 2 hours, 92% at 4 hours) in the presence of an equimolar concentration of BA. Two possibilities are suggested for the mechanism of BA protection against DMBA action.

Criteria for evaluating hormones in the 7,12-dimethylbenz[a]-anthracene-induced mammary tumor-rat experimental chemotherapy system.

Abstract: Two criteria were used to measure the effectiveness of hormones in the therapy of mammary tumors induced in Sprague-Dawley rats by 7,12-dimethylbenz[a]anthracene. These were complete regression of all tumors in the host and duration of complete remission. Well-established, growing mammary tumors were treated with testosterone propionate or 2 α -methyldihydrotestosterone propionate. There was no significant difference between the effects of the two androgens, at equivalent doses, with respect to production of complete remissions. However, the median for duration of complete remission in rats treated with 2 α -methyldihydrotestosterone propionate was significantly greater than for testosterone propionate. The results suggest that duration of remission is a useful adjunct for disclosing differences between compounds with similar abilities to cause tumor regression.

Unilateral development of ovarian tumour in thymectomized Swiss mice following a single injection of 7,12-dimethylbenz(a)anthracene at neonatal stage.

Abstract: Unilateral development of ovarian tumour in thymectomized Swiss mice following a single injection of 7,12-dimethylbenz(a)anthracene at neonatal stage

Tumors Developing in Oophorectomized Sprague-Dawley Rats after a Single Gastric Instillation of 7,12-Dimethylbenz(a)anthracene

Abstract: The present report describes the various types of tumors which developed in female Sprague-Dawley rats oophorectomized at age 46 days and fed a single dose of 20 mg 7,12-dimethylbenz( a )anthracene one week later. This method, which is known to induce breast carcinoma invariably in normal female rats of this strain, produced mammary cancer in only 5% of the oophorectomized rats, after a period of observation of about a year. In contrast, a high percentage of rats presented tumors of the ear duct (59%), neurofibrosarcomas of the ear lobe (64%), and various tumors of the skin and skin appendages (22%). The appearance of these extramammary tumors may be due in part to the longer lifespan of the rats because they escaped the lethal effects of breast carcinoma. However, a relationship between carcinogenic reactivity of the skin and the endocrine status of the host cannot be ruled out.

Suppression of Cellular Activity in the Reticuloendothelial System of the Rat by 7,12-Dimethylbenz(a)anthracene

Abstract: A single feeding of 7,12-dimethylbenz(a)anthracene (DMBA) (112 or 133 mg/kg) to female Sprague-Dawley rats, age 50 days, induced maturation arrest at the proerythroblast, promyeloblast, and promegakaryocytoblast level in bone marrow, depletion of thymic lymphocytes, and disorganization of the lymphoid follicles in the spleen. The peripheral blood reflected these changes. A decrease in lymphocytes was first observed on Day 2 after DMBA. At this time the total granulocyte count was increased. Lymphocytopenia and granulocytopenia were maximal on Days 5 and 6, but granulocytopenia was more profound. Thrombocytopenia and its attendant hemorrhagic phenomena were maximal between Days 9 and 15. Morphologic changes indicative of damage were first apparent in marrow on Day 3 and of recovery from damage on Day 9; regenerative changes occurred rapidly after Day 15 and were virtually complete by Day 25. There was no evidence for direct damage to the formed elements in peripheral blood by this hydrocarbon. These changes closely mimic those induced by radiation and are probably the consequence of damage to DNA of the proerythroblast, myeloblast, and megakaryoblast precursors.

Action of Drugs Affecting the Functioning of the Adrenal Cortex on Adrenal Necrosis Induced by 7,12-Dimethylbenz(a)anthracene and Its 7-Hydroxymethyl Derivative in Rats

Abstract: Drugs with inhibitory actions on adrenal corticosteroid synthesis were given to young adult female Sprague-Dawley rats prior to the administration of the adrenocorticolytic agents 7,12-dimethylbenz(a)anthracene or its metabolite 7-hydroxymethyl-12-methylbenz (a)-anthracene. Adrenal necrosis induced by both polycyclic compounds was prevented by Su 4885 (Metopirone), Su 9055 and Su 10603, but not by Elipten and AY 9944. No correlation was found between the reported action of a drug on steroid synthesis and its ability to protect against adrenal necrosis. Pretreatment of rats with ethionine abolished the protective action of the Su compounds. It is concluded that the mechanism by which these drugs protect the adrenal glands from necrosis is primarily associated with their ability to stimulate drug-metabolizing enzymes in the liver and not with their action upon adrenal corticosteroid synthesis. (Endocrinology 82: 1217, 1968)

Adrenal lipid and plasma corticosterone depletion after 7,12-dimethylbenz (a) anthracene administration to the albino rat.

Abstract: Fluorometrische Messungen zeigten eine Abnahme von Plasmacorticosterone (CCS). Die Bedeutung dieser Resultate fur theoretische Aspekte der Karzinogenese wird diskutiert.

Auto-antibody to 7,12-dimethylbenz(a)anthracene-induced leukemic cells in rats as detected by immune adherence.

Abstract: Sixteen Long-Evans rats with leukemias induced by 7,12-dimethylbenz(a)anthracene were studied for evidence of naturally occurring immunologic responses to their own leukemic cells with an immune adherence hemagglutination technique which was designed to detect fresh serum auto-antibodies to the membrane of the leukemic cells. Auto-antibodies to the cell membranes were found in 14 out of 16 rats, but were not demonstrable in the other two rats. Autochthonous thymus cells used as controls did not show positive immune adherence hemagglutination reactions with their own sera, nor did the leukemic cells show positive reactions with the pooled normal rat serum. These findings suggest a possibility that the leukemic rats are able to produce humoral antibodies against membrane-specific antigens of autochthonous leukemic cells.

Enhancement of 7,12-dimethylbenz(a)anthracene leukaemogenesis in mice by neonatal injection of cortisone acetate.

Abstract: Enhancement of 7,12-dimethylbenz(a)anthracene leukaemogenesis in mice by neonatal injection of cortisone acetate

7,12-Dimethylbenz(a)anthracene-induced Adrenocortical Necrosis and Its Inhibition by Metopirone (SU4885)

Abstract: Summary Subcutaneous injection of 40 mg of Metopirone ditartrate in aqueous solution inhibited the induction of adrenocortical necrosis by 5 mg of 7,12-dimethylbenz(a)anthracene (DMBA), given intravenously as an oil emulsion 30 minutes before or after the Metopirone. No such inhibition was observed when the interval between injections of the agents was one hour or more. Two doses of 2.5 mg of DMBA emulsion injected simultaneously or not more than 30 minutes apart induced adrenocortical necrosis, but these doses were ineffective when there was one hour or more between them.