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Purpose: 17-(Allylamino)-17-demethoxygeldanamycin (17AAG), a benzoquinone antibiotic, down-regulates oncoproteins by binding specifically to heat shock protein 90 (HSP90). We did a phase I study of 17AAG to establish the dose-limiting toxicity and maximum tolerated dose and to characterize 17AAG pharmacokinetics and pharmacodynamics. Experimental Design:(More)
PURPOSE Cisplatin adducts to nuclear DNA (nDNA) are felt to be the molecular lesions that trigger apoptosis, but the mechanism linking nDNA adduct formation and cell death is unclear. Some literature in the last decade has suggested a possible direct effect of cisplatin on mitochondria independent of nDNA interaction. In this study, we define separately the(More)
Platinum-based chemotherapeutic agents, such as carboplatin and cisplatin, are effective against many human tumors, but their use may be limited by a high incidence of ototoxicity. Delayed administration of the chemoprotective agent sodium thiosulfate (STS) reduces the ototoxicity of carboplatin in a guinea-pig model, when given up to 8 h after the(More)
Cisplatin is a potent cytotoxic agent that functions as a bivalent electrophile, forming both interstrand and intrastrand DNA cross-links. Cisplatin-mediated DNA damage results in cell cycle arrest and initiation of apoptotic cell death. Increased cellular glutathione concentrations have been closely correlated with cisplatin resistance but do not reduce(More)
PURPOSE The primary objective was to establish the dose-limiting toxicity (DLT) and recommended phase II dose of 17-(allylamino)-17-demethoxygeldanamycin (17AAG) given twice a week. EXPERIMENTAL DESIGN Escalating doses of 17AAG were given i.v. to cohorts of three to six patients. Dose levels for schedule A (twice weekly x 3 weeks, every 4 weeks) were 100,(More)
PURPOSE Heat shock protein 90 (Hsp90) is essential for the posttranslational control of many regulators of cell growth, differentiation, and apoptosis. 17-N-Allylamino-17-demethoxygeldanamycin (17-AAG) binds to Hsp90 and alters levels of proteins regulated by Hsp90. We conducted a phase I trial of 17-AAG in pediatric patients with recurrent or refractory(More)
Histone modifications and DNA methylation are epigenetic phenomena that play a critical role in many neoplastic processes, including silencing of tumor suppressor genes. One such histone modification, particularly at H3 and H4, is methylation at specific lysine (K) residues. Whereas histone methylation of H3-K9 has been linked to DNA methylation and(More)
BACKGROUND Previous studies indicate that suramin may be an active agent for treatment of solid tumors. The clinical use of suramin is complicated by a broad spectrum of toxic effects and complex pharmacology. Studies have suggested that the dose-limiting neurotoxicity of this agent is closely related to sustained plasma drug concentrations of 350(More)
We performed a phase I study of menogaril to determine if dosage reduction was required in patients with hepatic dysfunction and if the relationship between pharmacokinetics and leukopenia, previously defined in patients with normal hepatic and renal function, was altered. Eighteen patients received 27 courses of menogaril, of which 26 were evaluable for(More)
Hexamethylene bisacetamide (HMBA), a potent differentiating agent, was administered to patients with refractory malignant tumors. Thirteen patients received 30 evaluable courses. HMBA was given by continuous i.v. infusion for 5 days. Therapy was repeated every 28 days, if patients had recovered from toxicity. The starting dose was 24 g/m2/day. Because our(More)