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Ethylbis(2,2-dimethyl-1-aziridinyl)phosphinate (AB-163) was used to treat 27 patients in a phase I trial. The limiting toxicity on a weekly schedule of IV administration involved nausea and vomiting associated with a variety of cholinergic side effects, including possible seizures. A starting dose of 300--400 mg/M2/week is suggested for a Phase II trial. One partial response in a patient with squamous-cell carcinoma of the cervix metastatic to the lungs was seen. [ABSTRACT FROM AUTHOR]

The article examines the effect of pyran copolymer on dimethylbenz-a-anthracene (DMBA) experimental oral carcinogenesis in the golden Syrian hamster. The results indicate that none of the hamsters from the control group or pyran copolymer alone had histological evidence of carcinoma or precancerous transformation. Under the conditions set forth, pyran copolymer inhibited the carcinogenic effect of DMBA during the initiation phase. It is unclear what the mechanism of the inhibitory effect is.

Dehydroepiandrosterone (DHEA), an adrenal cortex hormone secreted in large quantities in humans, protects cells of the clonal mouse hippocampal cell line HT-22 against the excitatory amino acid glutamate (5 mM), and amyloid beta-protein (2 microM) toxicity in a dose-dependent manner with optimum protection obtained at 5 microM concentration of DHEA. The protective effects of DHEA appear to be specific in that other related steroids and metabolites of DHEA, such as 5-androstene-3beta,17beta-diol, etiocholan-3alpha-ol-17-one, etiocholan-3beta-ol-17-one, testosterone, and 5alpha-androstane-3, 17-dione, offered no protection even at 50 microM concentrations. In addition, using immunocytochemical techniques, we observed that 20 hr of treatment with 5 mM glutamate remarkably increased glucocorticoid receptor (GR) nuclear localization in neuronal cells. Interestingly, 5 microM DHEA treatment for 24 hr, followed by 5 mM glutamate treatment for 20 hr almost completely reversed the copious nuclear localization of GR observed by glutamate treatment alone. Results obtained suggest that DHEA protects hippocampal neurons, at least in part, by its antiglucocorticoid action via decreasing hippocampal cells nuclear GR levels.

Dark-cycle, night administration of the pineal hormone melatonin in drinking water to aging mice (15 months of age) prolongs survival of BALB/c females from 23.8 to 28.1 months and preserves aspects of their youthful state. Similar results were seen in New Zealand Black females beginning at 5 months and C57BL/6 males beginning at 19 months. As melatonin is produced in circadian fashion from the pineal, we grafted pineals from young 3- to 4-month-old donors into the thymus of 20-month-old syngeneic C57BL/6 male recipients, and a 12% increase in survival was induced. Prolongation of survival was also seen on pineal transplant to the thymus in C57BL/6, BALB/cJ, and hybrid female mice at 16, 19, and 22 months. In all studies, the endogenous pineal of grafted mice was left in situ. Pineal grafted aged mice display a remarkable maintenance of thymic structure and cellularity. Preservation of T-cell-mediated function, despite age, as measured by response to oxazolone is seen. Other evidence suggests that melatonin and/or pineal-related factors could produce their effects through an influence on thyroid function. These data indicate that pineal influences have a place in the physiologic regulation of aging.

Dehydroepiandrosterone (DHEA) is an endogenous steroid having a wide variety of biological and biochemical effects. In the present study, we have examined the role of DHEA on various rodent models of experimental hypertension. Sprague-Dawley rats were given subcutaneous injections of 1.5 mg dexamethasone every alternate day, resulting in an increase in systolic blood pressure within 1 wk. Interestingly, administration of a pharmacological dose of 1.5, 3, or 7.5 mg DHEA along with dexamethasone prevented dexamethasone-induced hypertension in a dose-dependent manner. DHEA had no effect on the hypertension induced by deoxycorticosterone acetate (DOCA)-salt administration using uninephrectomized rats or on the genetic model of spontaneously hypertensive rats. Dexamethasone administration resulted in a significant weight loss in rats, which was not prevented by simultaneous administration of DHEA. These results indicate that dexamethasone-mediated weight loss may involve mechanisms separate from its hypertensive action. Dexamethasone treatment resulted in a significant decrease in food consumption that was not reversed by DHEA. It is concluded that DHEA at doses above physiological levels when given subcutaneously has no effect on DOCA-salt or a genetic model of hypertension but has a beneficial effect on dexamethasone-induced hypertension.

Dehydroepiandrosterone (DHEA), the native clinical steroid and steroid precursor, may have a targeted physiologic role. A high affinity (Kd 2.3nM) and steroid specific [3H] DHEA binding macromolecule in male Sprague-Dawley rat hepatic cytosol suggests that DHEA may have receptor mediated physiologic action. 3[H] DHEA binding was highest in the liver followed by kidney and testis cytosols. Sulfhydryl reagents such as N-ethylmalemide and iodoacetamide inhibited the binding of [3H]DHEA by up to 60-70%. The DHEA-macromolecular complex was stable at 35 degrees C. and addition of 5mM molybdate or 0.3M KCl increased stability. Interestingly, rat liver cytosol, specific binding at 4 degrees C increased by almost 40-50% with addition of 0.1M NaSCN or 0.3M KCl. Sucrose gradient analyses showed a 7-8 S macromolecular complex in the low salt and 3-4 S complex under high salt conditions. The [3H] DHEA- macromolecular complex shows minimal temperature dependent activation in vitro at 25 degrees C as judged by binding to DNA-cellulose. The results suggest a specific high affinity macromolecule for DHEA in rat liver cytosol with unique physicochemical properties.

A combined intraoperative and postoperative adjuvant program of 5 minus Fluorouracil (5 FU) for patients undergoing "curative" resection for adenocarcinoma of the colon and rectum was initiated as a randomized clinical trial in January 1968. Patients at the Medical College of Virginia and the University of Virginia were randomly assigned to an intraluminal 5 FU or intraluminal control (Saline) group and were so treated at the time of surgical resection if findings at operation indicated that all gross neoplastic disease could be resected. Patients with operative findings denoting incurability were eliminated from the study after surgical exploration. Those patients receiving intraluminal 5 FU (30mg/kg) received intravenous 5 FU (10mg/kg) on each of the two first postoperative days and 5 subsequent postoperative courses of oral 5FU (90 mg/kg in each 18 day course) over a one year period. By December 31, 1973 (6 years) 156 patients undergoing "curative" resection were entered into the study. SU therapy with the control or "No Treat" group reveal no significant benefit from this intensive adjuvant course of 5 FU thus far. Continued assessment of these patient groups and their subgroups will be required to develop confidence in these findings but the data thus far suggest no potential benefit from this particular adjuvant program.

A significant protective effect of a native adrenal steroid, dehydroepiandrosterone (DHEA), was demonstrated in studies of two lethal viral infection models in mice: systemic coxsackievirus B4 and herpes simplex type 2 encephalitis. The steroid was active either by long-term feeding or by a single subcutaneous injection. A closely related steroid, etiocholanolone, was not protective in these models. Histopathological analysis, leukocyte counts, and numbers of spleen antibody forming cells in the coxsackievirus B4 model suggests that DHEA functions by maintaining or potentiating the immune competence of mice otherwise depressed by viral infection. DHEA was not effective in genetically immunodeficient HRS/J hr/hr mice and did not demonstrate antiviral activity in vitro. While the molecular basis for DHEA's effect on the immune system is not known, studies by others suggest that it may counteract the stress related immunosuppressive effects of glucocorticoids stimulated by viral infection. Because DHEA is a native steroid that has been used clinically with minimal side effects, the utility of DHEA in the therapeutic modulation of acute and chronic viral infections including the acquired immune deficiency syndrome deserves intensive study.