Cancer research
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The plasma and cerebrospinal fluid (CSF) pharmacokinetics of arabinosyl-5-azacytidine (AAC) were studied in rhesus monkeys following a 15-min, 1-h, or 12-h i.v. infusion of 200 mg/kg. No clinically significant toxicity was observed with these schedules. The plasma elimination of AAC is rapid and characterized by a triphasic decay with t1/2 alpha = 3.6-5.4 min, t1/2 beta = 18-24 min, and t1/2 gamma = 94-144 min for the above infusion schedules. ⋯ A triexponential equation modeling the disappearance of AAC was constructed from the in vivo experimental data. Use of this equation in computer-aided simulations of current Phase I doses and schedules of AAC correctly predicts the human plasma concentrations which have been observed. The preclinical pharmacokinetic data provided here may be useful in helping to develop rational human studies with specific concentration x time goals.
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Adoptive immunotherapy with interleukin 2 (IL-2) and lymphokine-activated killer (LAK) cells (IL-2/LAK) is a technically demanding cancer therapy dependent upon large scale isolation and culture of lymphocytes. An important question is whether this technology can be accomplished routinely outside of highly specialized centers. In addition, no systematic examination of laboratory correlates of IL-2/LAK therapy in humans has been reported to date. ⋯ Neither tumor reduction nor clinical toxicity correlated with dose or with cytolytic activity of LAK cells, or with other laboratory parameters including base-line lymphocyte count and IL-2-induced lymphocytosis. We conclude: (a) large quantities of LAK effector cells with tumoricidal activity can be generated routinely at different centers; (b) neither in vitro LAK activity nor numbers of LAK cells infused were predictive of clinical efficacy or toxicity. There is a need to identify other laboratory or clinical parameters more predictive of IL-2/LAK therapeutic efficacy or toxicity.
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Studies of V79-171 cells were undertaken to determine what extracellular or intracellular derivative of the drug WR-2721 is associated with radioprotection. The effect of preincubation at 23 +/- 1 degree C with WR-2721, and with derivatives of WR-2721 produced in medium containing alkaline phosphatase, upon survival of cells following subsequent gamma-irradiation was examined. It was established that WR-2721, WR-1065, WR-33278, WRSSCys, and other disulfide forms produced by reactions of WR-1065 with the medium do not provide significant protection when present only extracellularly. ⋯ None of the drug forms produced significant cytotoxicity under the conditions used. It was concluded that it is the cellular level of WR-1065 at the time of irradiation which determines protection. The results are consistent with protection mechanisms involving scavenging of hydroxyl radicals, hydrogen atom transfer to DNA radicals, depletion of oxygen near DNA, enhancement of rapid biochemical repair processes, or some combination of these mechanisms.
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The HER2/neu protooncogene was found to be amplified in 6 of 109 primary adenocarcinoma tumors. No HER2/neu amplification was found in 29 other primary nonadenocarcinomatous tumors. ⋯ Moreover, this tumor expressed an aberrant HER2/neu polypeptide with a molecular weight of 190,000, which is larger by approximately 5,000 than the molecular weight of the normal HER2/neu protein. The aberrant HER2/neu protein was immunoprecipitated with site-specific antibodies against a synthetic peptide from the COOH-terminal end of the normal HER2/neu protein; it also displayed intrinsic protein tyrosine kinase activity leading to self-phosphorylation.
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Swainsonine, an indolizidine alkaloid, has been found to inhibit the experimental metastasis of B16-F10 melanoma cells when administered systemically to syngeneic C57BL/6 mice. The inhibition was both potent and dose dependent with greater than or equal to 80% reduction in pulmonary colonization being observed after only 24-h exposure to 3 micrograms/ml of swainsonine in drinking water. ⋯ These results indicate (a) an absolute requirement for a functional NK cell population in order for swainsonine to exert its inhibitory effects on experimental metastasis, and (b) that the antimetastatic activity of swainsonine is mediated primarily through the ability of the drug to augment NK cell reactivity. On the basis of these findings, swainsonine can be classified as a new immunomodulator that has the ability, at least in a prophylactic setting, to block tumor metastasis.