DBA/2, BALB/c or (BALB/c X DBA/2)F1 (CDF1) mice of both sexes were treated for 1 week with a dietary hepatocarcinogenic tryptophan pyrolysate component (Trp P-1 or Trp P-2), and the activity of hepatic microsomal enzyme(s) for mutagenic activations of Trp P-1 and Trp P-2 were assessed by means of a mutation test with Salmonella typhimurium TA98. In both Ah-responsive (BALB/c and CDF1) and Ah-nonresponsive (DBA/2) mice, the dietary treatment with Trp P-1 or Trp P-2 resulted in a significant increase of the enzyme activity for mutagenic activations of Trp P-1 and Trp P-2 in females but not in males, except the case of male BALB/c mice treated with dietary Trp P-1. Also induction of enzyme(s) in female mice was suppressed by an administration of testosterone. The induced hepatic microsomal enzyme(s) was demonstrated to be cytochrome P-450 isozyme(s) (mol. wt of 55,000 daltons) by immunoblots with use of an anti-rat cytochrome P-448 monoclonal antibody and by selective inhibition of the activity by addition of 7,8-benzoflavone into the mutation assay system. These findings indicate that carcinogenic aromatic amines such as Trp P-1 and Trp P-2 are able to induce hepatic cytochrome P-450 isozyme(s) not only in Ah-responsive mice (BALB/c and CDF1) but also in Ah-nonresponsive DBA/2 mice and that the cytochrome P-450 induction is controlled by androgen(s).
The effect of recombinant human tumor necrosis factor-alpha (rhTNF-alpha) on anti-tumor activity of adriamycin entrapped in small unilamellar liposomes (ADM-Lip) has been studied using BALB/c mice bearing subdermal Meth-A fibrosarcoma. Accumulation of i.v. injected ADM-Lip, but not of free ADM, into tumor tissue was augmented by a single i.v. injection of rhTNF-alpha. The maximum effect of rhTNF-alpha was expressed when it was injected 1 hr before ADM-Lip. This rhTNF-alpha treatment did not result in increased accumulation of ADM-Lip in normal organs. Based on these results, we treated mice bearing Meth-A tumor with rhTNF-alpha and then with ADM-Lip 1 hr later. By 2-cycle treatments using this regimen, tumor growth was markedly inhibited, and 5 out of 13 mice tested were cured of tumor, while treatment with rhTNF-alpha alone, ADM alone, ADM-Lip alone or rhTNF-alpha plus ADM resulted neither in prolongation of survival time nor in cure of mice. Our results indicate that ADM-Lip can express a potent and systemic anti-tumor activity after pretreatment of animals with TNF, but only when administration of these drugs is appropriately timed.
Regulation by fetal hypothalamus of adrenocorticotrophic and thyrotrophic function of the fetal anterior hypophysis in the rat was studied by: (1) destruction of the fetal hypothalamic area with an electrocoagulator, (2) compression of the fetal brain bv injected uaraffin into the fetal skull and (3) induction of fetal exencephaly by hypervitaminosis A in the mother.The body weight of fetuses in which the hypothalamus was damaged was significantly less than that of littermate controls. Volume of the anterior hypophysis was small in fetuses injected with paraffin. The anterior hypophyses were present in all exencephalies, and showed abnormal forms but no reduction in volume. The adrenals were very small in all fetuses in which the hypothalamus was damaged, accompanied by conspicuous shrinkage of cortical cells, while the thyroids were not changed in volume. The height of the follicular cells decreased slightly.The observations suggest that in the late period of fetal life in rats, the hypophysial-adrenal system is regulated largely by the hypothalamus, but that the hypophysial-thyroid system is not fully under the control of the hypothalamus.During the late period of fetal life in the rat, the hypophysis regulates the growth and functioning of the adrenal and thyroid. spaces of capillaries on the surface of the median eminence (Kobayashi, Kobayashi, Kaibara and Ajika, '68). Recently, Jost, Dupouy and Monchamp ('66) reported that complete removal of the hypothalamus by decerebration of a fetal rat caused a retardation of adrenal growth and that the effect was prevented by administering hypothalamic extracts. Subsequently, Jost and Geloso ('67) showed that the same surgery on a fetus in a mother rat treated with propylthiouracil failed to prevent a hypertrophy of the fetal thyroid. This hypertrophy does not occur when the fetus is hypophysectomized by decapitation (Noumura, '59) : this means that the hypertrophy does not depend on maternal TSH across the placenta but largely on fetal TSH. These findings suggest that the hypothalamus is necessary for adrenal but not thyroid function in the fetal rat.The present work was designed to extend these studies. The experiments involved (1) destruction of the fetal hypothalamic area with an electrocoagulator, (2) com-
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.