Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The anti-drug resistance effect of three derivatives (AR-1, AR-2 and AR-3) of [1,2,5-trimethyl-4-phenyl-4-beta-(N,N-disubstituted-ethylamino)] piperidines, that were evaluated as calcium and calmodulin antagonists, was studied on doxorubicin (ADM) and vincristine (VCR) resistant Sarcoma-45 inoculated rats. Treatment with ADM (5 mg/kg) or VCR (3 mg/kg) alone, as well as with AR-1, AR-2 or AR-3 (50 mg/kg) alone, had no effect on tumor growth. However, AR-2 in dose 50 mg/kg (calmodulin antagonist), but not AR-1 and AR-3 (calcium channel blocker), administered with ADM (5 mg/kg) or VCR (3 mg/kg), significantly suppressed tumor growth 80% and 70%, respectively. Two rats treated with ADM/AR-2 and one treated with VCR/AR-2 were cured. 170 kDa protein was purified from sarcoma-45 tumor cells to apparent homogeneity by successive steps of phosphocellulose, DEAE-cellulose, and AR-2-coupled sepharose chromatography. The protein proved to be immunopositive with the P-glycoprotein-specific monoclonal antibody. It is concluded that the effect of AR-2 can be explained by both hydrophobic and electrostatic interaction with a protein target (170 kDa P-glycoprotein) in resistant sarcoma-45 tumor cell's membrane.
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PMID:Reversal of drug resistance in sarcoma-45 by the new calmodulin antagonist--trihydrochloride of [1,2,5-trimethyl-4-phenyl-4-beta-[N-(beta-ethylamino)-N-4'-methoxybe nzy l]-ethylamino] piperidine (AR-2). 1063 81

Trabectedin [Ecteinascidin 743, Yondelis, ET 743, NSC 684766] is a tetrahydroisoquinoline alkaloid derived from the Caribbean marine tunicate, Ecteinascidia turbinata. The drug is being developed by PharmaMar (Zeltia) in partnership with Johnson & Johnson Pharmaceutical Research & Development LLC. It was synthetically isolated and developed by the University of Illinois and licensed to PharmaMar; the company has completed the hemisynthesis of agent. Trabectedin interacts with the minor groove of DNA and alkylates guanine at the N2 position, which bends towards the major groove. In this manner, it is thought that the drug affects various transcription factors involved in cell proliferation, particularly via the transcription-coupled nucleotide excision repair system. Trabectedin blocks the cell cycle at the G(2) phase, while cells at the G(1 )phase are most sensitive to the drug. It also inhibits overexpression of the multidrug resistance-1 gene (MDR-1) coding for the P-glycoprotein that is a major factor responsible for cells developing resistance to cancer drugs. The agent is also thought to interfere with the nucleotide excision repair pathways of cancer cells, suggesting that it could be effective in the treatment of many cancer types including melanoma and sarcoma, as well as lung, breast, ovarian, endometrial and prostate cancers; clinical evaluations are underway in these indications. PharmaMar and Ortho Biotech Products (Johnson & Johnson) entered into an agreement in August 2001 for the joint development and commercialisation of trabectedin. PharmaMar retains commercialisation rights in Europe, including Eastern Europe. Ortho Biotech will market the product in the US, Japan and the rest of the world; Tibotec Therapeutics (a division of Ortho Biotech) will commercialise it in the US. PharmaMar will receive an initial payment from Ortho Biotech plus future milestone and royalty payments linked to development targets and sales; the upfront payment would be approximately 20 million US dollars with royalties contributing 10-20% of total sales of the drug. Although details of the licensing transaction for trabectedin were undisclosed, analysts estimate the figure to be around 100 million US dollars. Previously, PharmaMar signed an agreement granting Bristol-Myers Squibb the option to evaluate and develop as many as 12 of PharmaMar's marine-derived anticancer compounds on an exclusive worldwide basis. However, it appears that Bristol-Myers Squibb had chosen not to exercise the option. Trabectedin is undergoing clinical trials in soft tissue sarcoma (Sarcoma in the Phase table), ovarian, breast, endometrial, prostate and non-small-cell lung cancers. PharmaMar indicated in January 2004 that it intends to launch trabectedin in one of these indications in 2006. PharmaMar raised funds from a round of financing in June 2005 that will be used to fund further clinical trials of its anticancer products, including trabectedin. The US FDA granted trabectedin orphan drug status for ovarian cancer in April 2005. Trabectedin also received orphan drug status from the European Commission for the treatment of ovarian cancer in October 2003. This followed a positive opinion by the Committee for Orphan Medicinal Products (COMP) of the EMEA. Trabectedin has undergone a phase II study for the second- or third-line treatment of ovarian cancer in Europe (England and Belgium), the US and Canada. The trial was initiated in October 2002 and evaluated a weekly schedule of trabectedin (0.58 mg/m(2)) via IV infusion for 3 weeks followed by a week of rest. Final results from this study have been presented. A separate phase II trial evaluating the antitumour activity of trabectedin as a second-line therapy in advanced ovarian cancer was conducted by researchers at the Southern Europe New Drugs Organization (SENDO) in Milan, Italy. PharmaMar and Johnson & Johnson are conducting a pivotal (STS-201) trial to compare a weekly and daily dosing regimen of trabectedin among patients with advanced or metastatic soft tissue sarcoma who are unresponsive to standard chemotherapy of doxorubicin and ifosfamide. The randomised, multicentre, open-label trial has completed enrolment of 270 patients during the second quarter of 2005. Positive data from the STS-201 trial have been announced. An independent data monitoring committee has found that interim data supports a positive trend in time to disease progression favouring patients receiving the daily dosing regimen. Consequently, all patients have been offered the option of switching to the daily regimen. Final results from the STS-201 trial will form the basis of MAA re-submission with European regulatory authorities. PharmaMar has held a pre-submission meeting with the EMEA and has presented a formal letter of intent to file for approval of trabectedin for soft tissue sarcoma. Previously, PharmaMar first filed for EU registration of trabectedin for treatment of advanced soft tissue sarcoma in November 2001, which was accepted for review by the EMEA and Swiss Health Authorities. However, the CPMP confirmed its recommendation not to grant trabectedin marketing authorisation in November 2003 following PharmaMar's appeal against the CPMP's negative opinion first announced in July 2003; the opinion was adopted by a majority vote rather than by consensus. Trabectedin was granted orphan drug status in Europe for recurrent soft tissue sarcoma in 2001. It was also granted orphan drug status by the FDA for the same indication in October 2004. Phase I studies are being conducted to evaluate trabectedin in combination with doxorubicin and liposomal doxorubicin for the treatment of soft tissue sarcoma. PharmaMar is also conducting a phase I study of sequential paclitaxel followed by trabectedin in patients with soft tissue sarcoma. At additional dose levels, patients with other tumour types will be enrolled to assess the antitumour activity of the combination. The US NCI has approved and is partially funding a phase I clinical programme to determine the feasibility of using trabectedin to treat children with soft tissue sarcoma and bone sarcoma who are resistant to conventional therapies. PharmaMar has reported that trabectedin can be safely administered to children at doses up to 1100mg given as a 3-hour infusion, and that this dose will be used in further paediatric studies. Trabectedin has completed phase II studies for small round cell sarcoma and rhabdomyosarcoma, which are aggressive tumours occurring predominantly in children. A phase II study evaluating two dosing schedules of trabectedin has been conducted in patients with leiomyosarcomas or liposarcomas refractory to standard doxorubicin + ifosfamide chemotherapy. The study was conducted in Australia, Canada, Russia and the US.
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PMID:Trabectedin: Ecteinascidin 743, Ecteinascidin-743, ET 743, ET-743, NSC 684766. 1692 93

The aim was to evaluate the clinical impact of P-glycoprotein in primary non-metastatic high-grade osteosarcoma patients, treated with neoadjuvant chemotherapy protocols. P-glycoprotein was assessed by immunohistochemistry on paraffin-embedded tissue samples collected at time of diagnosis from 94 osteosarcoma patients, treated with the Italian Sarcoma Group/Scandinavian Sarcoma Group 1 (ISG/SSG 1) protocol. P-glycoprotein-positivity at diagnosis was found in 53/94 ISG/SSG 1 cases (56%) and emerged as the single factor significantly associated with an unfavourable outcome from survival and multivariate analyses. A comparative analysis of the subgroup of 94 patients considered for P-glycoprotein evaluation and the whole series of ISG/SSG 1 patients showed that this marker retained its prognostic value also in the latter group. In osteosarcoma patients treated with doxorubicin-based chemotherapy protocols, P-glycoprotein overexpression at diagnosis is an important adverse prognostic factor for outcome. P-glycoprotein evaluation can therefore constitute the basis for stratifying, at diagnosis, osteosarcoma patients for whom alternative treatments may be considered.
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PMID:May P-glycoprotein status be used to stratify high-grade osteosarcoma patients? Results from the Italian/Scandinavian Sarcoma Group 1 treatment protocol. 1708 85

Purpose. To investigate angiogenesis, multiple drug resistance (MDR) and proliferative activity as prognostic variables in patients suffering from osteosarcoma. Methods. Histologic biopsies from 117 patients treated in the period from 1972 through 1999 were immunohistologically investigated regarding angiogenesis (CD34), proliferative activity (MIB-1), and the expression of p53 and MDR (P-glycoprotein (Pgp); clones JSB-1, C494, and MRK16). Quantitative and semiquantitative scores of immunoreactive cells were analyzed statistically along with retrospectively obtained clinicopathologic variables. Results. Chemotherapy reduced the rate of amputations (P = .00002). The Pgp was overexpressed (score >/=2) in 48% of the primary, diagnostic biopsies, and high Pgp correlated with high Pgp in postsurgical specimens (P = .003). In contrast, no such associations were disclosed for estimates of angiogenesis (P = .64) and p53 (P > .32), whereas the MIB-1 index was reduced in the post-chemotherapy specimens (P = .02). The overall, disease-specific survival was 47%, increasing to 54% in patients receiving pre-operative chemotherapy. Statistical analyses showed prognostic impact exclusively by patient age and type of osteosarcoma. Discussion. The studied series of patients documented already prior to the chemotherapy era, a rather excellent survival and estimates of angiogenesis, proliferation, p53, and Pgp expressions, did not demonstrate sufficient power to serve as predictors of treatment response or survival.
Sarcoma 2008
PMID:Immunohistochemical Estimates of Angiogenesis, Proliferative Activity, p53 Expression, and Multiple Drug Resistance Have No Prognostic Impact in Osteosarcoma: A Comparative Clinicopathological Investigation. 1926 50