Differential alteration of cisplatin cytotoxicity and myelotoxicity by the paclitaxel vehicle cremophor EL

Abstract

Cremophor EL (CR), the paclitaxel vehicle, has previously been reported to alter the pharmacokinetics and/or pharmacodynamics of some anticancer drugs including paclitaxel. Several experimental and clinical studies suggested that cisplatin (CDDP) in combination with paclitaxel results in less hematological toxicity than anticipated. To reveal the role of CR in this important pharmacological interaction, we evaluated the interaction of CR with CDDP in vitro and in vivo using experimental Ehrlich ascites carcinoma (EAC) tumor. CR (1 microg/ml) significantly enhanced the in vitro cytotoxicity of CDDP in cultured EAC cells. This enhancement was not associated with a parallel increase in CDDP cellular uptake. In tumor-bearing mice, CR (2.5 ml/kg, i.v.) given in combination with CDDP (7 mg/kg, i.v.) did not significantly change CDDP pharmacokinetics, antitumor activity or nephrotoxicity. On the other hand, CDDP-induced hematological toxicity was significantly reduced by CR. This protective effect was related to CR-induced inhibition of cellular CDDP accumulation in bone marrow. This study presents evidence that CR may play an important role in the pharmacological interaction between CDDP and paclitaxel. The present data may suggest formulation of CDDP with CR for systemic treatment. Further studies are yet necessary to establish the clinical value of CR as a modifier for CDDP therapeutic index.

Pharmaceutics for the anaesthetist

“…Additionally, there have been other interesting effects observed after the administration of Cremophor‐containing drugs. The first was an observation that Cremophor EL favourably modifies the pharmacokinetics of a number of antineoplastic agents, with a resulting increase in antitumour efficacy of the drugs [49]. Another unusual effect of Cremophor is its capacity to modulate multidrug resistance (MDR).…”

Dose and schedule-finding study of oral topotecan and weekly cisplatin in patients with recurrent ovarian cancer

“…The third schedule was based on the preclinical observation that CrEL protected from cisplatin-induced haematological toxicity (Ma et al, 1996;de Vos et al, 1997;Badary et al, 2000). In these studies CrEL inhibited DNA adduct formation and the intracellular accumulation of cisplatin in human leukocytes, and in mice CrEL protected from cisplatin induced myelotoxicity.…”

Spectroscopic Study on the Reaction of L-Cysteine in Rh(PVP) Nanoparticle Colloidal Solution

“…The platinum group elements show a high reactivity for halogens and chalcogens. Many studies have been undertaken into the catalytic performance of platinum group metal halide and chalcogenide [1][2][3][4][5][6][7]. It is considered that the platinum group metal halide and chalcogenide have stable structures and we can use the platinum group metals as a remover for the halogen and chalcogen.…”