Cancer chemotherapy and pharmacology
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Cancer Chemother. Pharmacol. · Jan 2000
Pharmacokinetics and antitumor properties in tumor-bearing mice of an enediol analogue inhibitor of glyoxalase I.
The enediol analogue S-(N-p-chlorophenyl-N-hydroxycarbamoyl)glutathione (CHG) is a powerful, mechanism-based, competitive inhibitor of the methylglyoxal-detoxifying enzyme glyoxalase I. The [glycyl,glutamyl]diethyl ester prodrug form of this compound (CHG(Et)2) inhibits the growth of different tumor cell lines in vitro, apparently by inducing elevated levels of intracellular methylglyoxal. The purpose of this study was to evaluate the pharmacokinetic properties of CHG(Et)2 in plasma esterase-deficient C57BL/6 (Es-1e) mice after intravenous (i.v.) or intraperitoneal (i.p.) administration of bolus doses of CHG(Et)2. In addition, the in vivo antitumor properties of CHG(Et)2 were evaluated against murine B16 melanoma in these mice, and against androgen-independent human prostate PC3 tumor and human colon HT-29 adenocarcinoma in plasma esterase-deficient nude mice. ⋯ This is the first demonstration that a mechanism-based competitive inhibitor of glyoxalase I effectively inhibits the growth of solid tumors in mice when delivered as the diethyl ester prodrug.
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Cancer Chemother. Pharmacol. · Jan 2000
Evaluation of antidotes for extravasation injury produced by 6-hydroxymethylacylfulvene (MGI 114), a novel cytotoxic antitumor agent, in an intradermal toxicity model in rats.
MGI 114 (HMAF, 6-hydroxymethylacylfulvene) is a cytotoxic drug currently in phase II human clinical trials. As with other anticancer agents, inadvertent drug extravasation may result in perivascular irritation and/or necrosis. In this study the degree of soft tissue injury produced by MGI 114 after intradermal administration to rats was quantified and four potential antidotes for extravasation injuries caused by MGI 114 were evaluated. ⋯ DMSO provided near complete tissue protection from intradermal exposure to MGI 114. In this model MGI 114 and doxorubicin were found to produce similar soft tissue injuries, but MGI 114-induced lesions tended to show a more rapid resolution. Topical DMSO treatment was found to produce the most effective protection against MGI 114-induced local tissue irritation and necrosis.
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Cancer Chemother. Pharmacol. · Jan 2000
Multicenter Study Clinical TrialCarzelesin phase II study in advanced breast, ovarian, colorectal, gastric, head and neck cancer, non-Hodgkin's lymphoma and malignant melanoma: a study of the EORTC early clinical studies group (ECSG).
In a phase II trial, the activity of carzelesin, a cyclopropylpyrroloindole prodrug analog, was assessed. ⋯ At this dose and schedule carzelesin did not yield activity in the types of tumors studied.
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The identification of tumor-associated antigens recognized by cellular or humoral effectors of the immune system has opened new perspectives for cancer therapy. Different groups of cancer-associated antigens have been described as targets for cytotoxic T lymphocytes (CTLs) in vitro and in vivo: 1) cancer-testis (CT) antigens, which are expressed in different tumors and normal testis; 2) melanocyte differentiation antigens; 3) point mutations of normal genes; 4) antigens that are overexpressed in malignant tissues; and 5) viral antigens. Clinical studies with peptides derived from these antigens have been initiated to induce specific CTL responses in vivo. ⋯ Based on these observations, cytokines to enhance antigen and MHC class I expression in vivo are being evaluated to prevent immunoselection. Recently, a strategy utilizing spontaneous antibody responses to tumor-associated antigens (SEREX) has led to the identification of a new CT antigen, NY-ESO-1, which is regarded as one of the most immunogenic antigens known today inducing spontaneous immune responses in 50% of patients with NY-ESO-1-expressing cancers. Clinical studies involving antigenic constructs that induce both antibody and CTL responses will show whether these are more effective for immunotherapy of cancer.
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Cancer Chemother. Pharmacol. · Jan 2000
Randomized Controlled Trial Clinical TrialPretreatment with ranitidine does not reduce the bioavailability of orally administered topotecan.
The purpose of this randomized, two-period crossover study was to determine the pharmacokinetics of orally administered topotecan in the presence and absence of oral ranitidine. ⋯ Administration of ranitidine prior to oral topotecan resulted in a similar extent of absorption. A slightly faster rate of absorption of topotecan was also observed, which is unlikely to be of clinical significance. Dosage adjustments of orally administered topotecan should not be necessary in patients who are pretreated with ranitidine, an H2 antagonist, or another agent that comparably raises gastric pH.