Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cremophor EL, a polyloxyethylene castor oil derivative used clinically as a parenteral vehicle, inhibits protein kinase c activity in vitro. The tumor promoting agent TPA (12-0-tetradecanoylphorbol-13-acetate) activated protein kinase C and induced phosphorylation of cellular proteins of human myeloblastic leukemia ML-1 cells. Polypeptides of 56 KDa, 44 KDa, 37 KDa, 35 KDa and 31 KDa were particularly phosphorylated in response to TPA activation. However, the phosphorylations of these polypeptides, especially that of 37 KDa, were greatly reduced by treatment of the TPA-activated ML-1 cells with Cremophor EL. Cremophor EL also inhibited the growth of ML-1 cells. On the other hand, the TPA-induced cell differentiation in ML-1, which is considered a separate event from protein kinase C activation, was not affected by Cremophor EL. These studies suggest biological implications for the observed in vitro activity of Cremophor EL. The studies may also provide a mechanism for the Cremophor EL-associated cytotoxicities observed when it is used clinically as a parenteral vehicle.
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PMID:Cremophor EL inhibits 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced protein phosphorylation in human myeloblastic leukemia ML-1 cells. 174 8

Didemnin B is a depsipeptide extracted from the marine tunicate Trididemnin cyanophorum. This agent is a potent inhibitor of L1210 growth in vitro and has activity against murine B16 melanoma, P388 leukemia, and M5076 sarcoma in vivo. The results of preclinical toxicologic tests demonstrated abnormalities in clotting parameters thought to be secondary to drug-induced liver dysfunction. Thirty-five patients with advanced cancer received didemnin B according to a 5-day bolus schedule with dose levels ranging from 0.03 to 2.00 mg/m2/d. The dose-limiting toxicity was nausea and vomiting. Sporadic elevation of the hepatic enzyme level occurred but was not dose limiting. Two patients had anaphylactic symptoms possibly related to the 5% polyoxyethylated castor oil (Cremophor EL, BASF, Ludwigshafen, Germany) vehicle during the drug infusion. Clinical bleeding was not observed and myelosuppression was not significant. No partial or complete tumor responses were seen. The recommended Phase II dose for the 5-day schedule is 1.6 mg/m2/d.
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PMID:A phase I clinical trial of didemnin B. 193 1

Studies were carried out on two purpurins, NT2 and an analog, Sn.NT2H2. Both are photosensitizers, but the latter is substantially more effective against neoplastic cells in vivo. These hydrophobic dyes can be solubilized via Cremophor EL emulsions. We found both dyes to be approximately equitoxic to murine leukemia L1210 cells in culture, in terms of intracellular concentrations. But uptake of NT2 was 10-fold less efficient than Sn.NT2H2, i.e. a 10-fold higher extracellular level of NT2 was needed to produce an equitoxic response. Fluorescence measurements indicate that NT2 partitions to a very hydrophobic intracellular environments; its phototoxicity was related to inhibition of biosynthesis of DNA. In contrast, SN.NT2H2 was accumulated at more hydrophilic loci (the apparent dielectric constant is consistent with a membrane interface) and mediated photodamage at sites of membrane transport.
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PMID:Determinants of photosensitization by purpurins. 278 Aug 13

Paclitaxel, a novel diterpenoid compound, has been used by dissolving in Cremophor EL (polyoxyethylene castor oil) due to its poor aqueous solubility. Cremophor EL was shown to reverse multidrug resistant phenotypes of various cell lines as well as to reverse cross-resistance to paclitaxel of a multidrug resistant cell line in vitro. Thus, a study was carried out to determine the modifying activity of Cremophor EL on the antitumor activity of paclitaxel against P388 leukemia, adriamycin-resistant subline (P388/ADM) and vincristine-resistant subline (P388/VCR) in vivo. Dimethyl sulfoxide (DMSO) was used as a counterpart solvent. The results showed that, although no significant antitumor activity was observed by paclitaxel in both solvents against P388/ADM, a significantly higher antitumor activity was induced by paclitaxel dissolved in Cremophor EL-based solvent compared with DMSO-based solvent against P388/VCR. However, more significant difference in the antitumor activity of paclitaxel against P388 parental line was observed between two solvents and both resistant sublines showed an obvious cross-resistance to paclitaxel. Therefore, it appeared that cross-resistance reversing activity of Cremophor EL is not so high as to be detectable at in vivo level.
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PMID:[Study for modifying activity of solvents on antitumor activity of paclitaxel]. 790 93

Treatment of cancer patients with 3-h infusions of taxol formulated with Cremophor EL resulted in a marked decrease in the electrophoretic mobility of all plasma lipoproteins. Cremophor was fractionated by reverse-phase chromatography to determine which components were responsible for this behavior. Effects of different Cremophor fractions on reversal of multidrug resistance, amino acid transport, and cytotoxicity also were evaluated using murine leukemia cells in culture. Lipoprotein alterations were caused by Cremophor components of intermediate hydrophobicity, which also antagonized amino acid transport and decreased viability of murine leukemia cells. Cremophor components responsible for reversal of multidrug resistance were of greater hydrophobicity. The lipoprotein-altering components of Cremophor could be selectively removed without affecting either taxol solubilization or multidrug-resistant reversal.
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PMID:Fractionation of Cremophor EL delineates components responsible for plasma lipoprotein alterations and multidrug resistance reversal. 853 26

Paclitaxel, a recently approved antineoplastic agent, is cleared slowly from the peritoneal cavity after i.p. injection, and therefore appears to be promising for intracavitary therapy of malignancies confined to the peritoneal cavity. However the dose-limiting toxicity of Taxol, the clinical formulation of paclitaxel, was severe abdominal pain, likely caused by the excipients (Cremophor EL and ethanol) that are required to overcome low drug solubility. We tested the hypothesis that a liposome-based formulation could modulate paclitaxel toxicity independent of antitumor activity. The dose-dependence of toxicity and antitumor effect of paclitaxel liposomes was evaluated after i.p. administration against i.p. P388 leukemia. Liposomal paclitaxel showed antitumor activity similar to that of free paclitaxel (as Taxol), but was better tolerated by both healthy and tumor-bearing mice.
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PMID:Paclitaxel-liposomes for intracavitary therapy of intraperitoneal P388 leukemia. 894 23

Cremophor EL (CreEL), a polyethylene castor oil used as a vehicle for cyclosporin A and taxol, reverses P-glycoprotein-mediated drug resistance. The vehicle in an i.v. dosage form of PSC 833, [3'-keto-Bmt1]-[Val2]-cyclosporin, contains CreEL and has been presumed to have the potentiation of the reversal activity of PSC 833. To examine this possibility, we compared reversal activities of CreEL and PSC 833 against multidrug resistance (MDR) in vitro and in vivo. Both CreEL and PSC 833 inhibited P-glycoprotein-mediated efflux of [3H]vincristine from adriamycin-resistant myelogenous leukemia K562. The sensitization of multidrug-resistant cell lines to anticancer drugs by CreEL and PSC 833 was selective to MDR-related agents, suggesting a specific interference of the P-glycoprotein function by the two MDR modulators. The concentration-dependent activity of the modulators demonstrated that CreEL is at least 100 times less potent than PSC 833. The in vivo reversal effects of CreEL alone and PSC 833 in the vehicle were investigated in multidrug-resistant tumor-bearing mouse models. In vincristine-resistant P388 leukemia-bearing mice, neither i.v. nor i.p. administration of CreEL even at 1440 mg/kg enhanced the antitumor activity of adriamycin. The in vivo negligible activity of CreEL was confirmed in an HCT-15-bearing athymic mouse model. In contrast, PSC 833 significantly enhanced the antitumor activity of adriamycin in the in vivo models. The reversal activity of CreEL restricted to in vitro leads us to conclude that the vehicle containing CreEL did not potentiate the activity of PSC 833 in the tumor-bearing mouse models.
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PMID:Cremophor EL reversed multidrug resistance in vitro but not in tumor-bearing mouse models. 899 Nov 85

PG27, an active fraction purified from an extract of a Chinese herb, Tripterygium wilfordii hook f, was used to prevent graft-versus-host disease (GVHD) in a murine model. Lethally irradiated BALB/c (H-2(d)) recipients of B10.D2 (H-2(d)) donor grafts were given daily intraperitoneal injections of PG27 (40 mg/kg per day) for the first 35 days after transplantation. Control mice were given daily injections of solvent vehicle (Ethanol and Cremophor EL). All the control recipients (15/15) died of GVHD within 90 days, but all the recipients given prophylactic treatment with PG27 (15/15) survived beyond 100 days without any signs of GVHD. Furthermore, the GVHD-free recipients were used as donors, and their bone marrow and spleen cells were transplanted into lethally irradiated normal BALB/c (same party) or lethally irradiated normal C3H (H-2(k), third party) mice. Although 10 of 10 same-party recipients survived more than 100 days without any signs of GVHD, 10 of 10 third-party C3H recipients died of GVHD within 40 days. Further studies of PG27 in the murine BCL1 leukemia/lymphoma model demonstrated that animals treated with PG27 partially retained the graft-versus-leukemia (GVL) effect of the graft without GVHD. These results suggest that treatment with PG27 induces host-specific tolerance and retains the GVL effect of allogeneic marrow grafts. (Blood. 2000;95:705-710)
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PMID:PG27, an extract of Tripterygium wilfordii hook f, induces antigen-specific tolerance in bone marrow transplantation in mice. 1062 83

The study objective was to develop a formulation of elacridar to overcome its dissolution-rate-limited bioavailability. Elacridar is a P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) inhibitor that has been used to improve the brain distribution of drugs that are substrates of P-gp and BCRP. The chronic use of elacridar is restricted because of the poor solubility leading to poor oral bioavailability. A microemulsion formulation using Cremophor EL, Carbitol, and Captex 355 (6:3:1) was developed. The elacridar microemulsion was effective in the inhibition of P-gp and Bcrp in Madin-Darby canine kidney II-transfected cells. Friend Leukemia Virus Strain B (FVB) mice were used to determine the bioavailability of elacridar after a 10 mg/kg dose of elacridar in the microemulsion, intraperitoneally (i.p.) and orally (p.o.); and the absolute bioavailability was determined to be 1.3 and 0.47, respectively. Coadministration of elacridar microemulsion i.p. with p.o. erlotinib in FVB mice improved the erlotinib brain penetration threefold. The current study shows that a microemulsion formulation of elacridar is effective in improving the bioavailability of elacridar and is an effective inhibitor of P-gp and Bcrp, in vitro and in vivo. It offers an alternative to the suspension and allows a decrease in the dose required to achieve a significant inhibitory effect at the blood-brain barrier.
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PMID:Development and evaluation of a novel microemulsion formulation of elacridar to improve its bioavailability. 2333 25