Cancer chemotherapy and pharmacology
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Cancer Chemother. Pharmacol. · Feb 2007
Novel mechanisms of platinum drug resistance identified in cells selected for resistance to JM118 the active metabolite of satraplatin.
The goal of this study was to identify molecular determinants of sensitivity and resistance to JM118, the active metabolite of satraplatin, an orally bioavailable cisplatin analog that has activity in prostate cancer. ⋯ While the cellular defense mechanisms that protect cells against JM118 also mediate resistance to the other Pt drugs, these mechanisms are quite different from those commonly found in cells selected for resistance to cisplatin. JM118-resistant cells accumulate more rather than less Pt and rely on an intracellular detoxification mechanism different from that involved in cisplatin resistance. This is consistent with clinical evidence suggesting that satraplatin has activity in diseases in which cisplatin does not. In this model, JM118 resistance is associated with substantial collateral hypersensitivity to docetaxel, paclitaxel, and doxorubicin.
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Cancer Chemother. Pharmacol. · Feb 2007
Reproductive toxicity evaluation of a new camptothecin anticancer agent, CKD-602, in pregnant/lactating female rats and their offspring.
CKD-602 is a camptothecin anticancer agent that was recently developed by the Chong Kun Dang Pharmaceutical Co. (Seoul, Korea). This study examined the potential adverse effects of CKD-602 on pregnancy, delivery, and lactation in female Sprague-Dawley rats as well as on the pre- and postnatal development of their offspring. One hundred pregnant females were divided into four groups: three treatment groups and a control group. ⋯ In the medium dose group, only slight maternal toxicity including suppressed body weight and decreased food consumption was observed. There were no treatment-related effects on the maternal function and pre- and postnatal development in the low dose group. The no-observed-adverse-effect level (NOAEL) of CKD-602 for the dams are considered to be 5.7 microg/kg/day, however, the NOAEL for their offspring are estimated to be 17 microg/kg/day.
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Cancer Chemother. Pharmacol. · Jan 2007
Clinical TrialPharmacokinetics and tumor uptake of a derivatized form of paclitaxel associated to a cholesterol-rich nanoemulsion (LDE) in patients with gynecologic cancers.
A cholesterol-rich nanoemulsion termed LDE concentrates in cancer tissues after injection into the bloodstream. The association of a derivatized paclitaxel to LDE showed lower toxicity and increased antitumoral activity as tested in a B16 melanoma murine model. Here, the pharmacokinetics of LDE-paclitaxel oleate and the ability of LDE to concentrate the drug in the tumor were investigated in patients with gynecologic cancers. ⋯ Paclitaxel oleate associated to LDE is stable in the bloodstream and has greater plasma half-life and AUC than those for paclitaxel-cremophor. LDE concentrates 3.5 times more paclitaxel in malignant tissues than in normal tissues. Therefore, association to LDE is an interesting strategy for using paclitaxel to treat gynecologic cancers.
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Cancer Chemother. Pharmacol. · Jan 2007
Comparative StudyA pharmacokinetic and safety study of a novel polymeric paclitaxel formulation for oral application.
To investigate the pharmacokinetics, safety, and tolerability of a new oral formulation of paclitaxel containing the polymer polyvinyl acetate phthalate in patients with advanced solid tumors. ⋯ The AUC of the new polymeric paclitaxel formulation increased a factor 2 in combination with CsA, which confirms that CsA co-administration can also improve exposure to paclitaxel after oral administration of a polymeric formulation. Because of the delayed release of paclitaxel from this formulation, we hypothesize that a split-dose regimen of CsA where it is administered before and after paclitaxel administration will further increase the systemic exposure to paclitaxel up to therapeutic levels. The formulation was well tolerated at the dose of 100 mg without induction of severe toxicities.
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Cancer Chemother. Pharmacol. · Jan 2007
A phase I study of the safety and pharmacokinetics of edotecarin (J-107088), a novel topoisomerase I inhibitor, in patients with advanced solid tumors.
To assess the maximum tolerated dose, safety, and pharmacokinetic (PK) profile of escalating doses of the novel topoisomerase I (topo I) inhibitor edotecarin (J-107088) given as a 2-h intravenous (IV) infusion once every 21 days in patients with advanced solid tumors who had not responded to standard therapy. ⋯ The recommended Phase II dose of edotecarin is 13 mg/m(2) once every 21 days. The toxicities in this study were those typical of cytotoxic chemotherapy and less severe than those associated with other topo I inhibitors. The observed safety profile and preliminary evidence of clinical benefit warrant further investigation of this drug as monotherapy or part of combination therapy in patients with solid tumors.