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)

Drug sensitivities of 76 human tumor lines/nude mice to 9 anti-cancer drugs were tested. Human tumor lines include pancreas cancers, brain tumors, neuroblastomas and etc. Tested anti-cancer drugs include MMC, 5-FU, and etc. When clinically equivalent dose of anti-cancer drugs were administered, drug sensitivities of these carcinomas were well correlated with clinical one, although blood brain barrier must be considered when brain tumors were tested. Our drug sensitivity panel revealed that cancers originated from the same organ showed the same tendency of drug sensitivity. Therefore, our drug sensitivity panel is thought to be useful to know the anti-cancer spectrum of newly developed anti-cancer drugs. Our panel is also useful to study the chemotherapy of rare cancers, because clinical studies of rare cancers are difficult. Expression of P-glycoprotein is correlated with drug resistance when treated with CED, but is not correlated with those when treated with MTD (maximum tolerate dose). That is human tumor lines with P-glycoprotein detected by C219 monoclonal antibody showed resistance to ADR, VCR and VLB when treated by CED, but the relationship was not observed when treated with MTD.
 ...
PMID:[Drug sensitivity panel of human cancers transplanted in nude mice]. 185 16

Older patients with acute myelogenous leukemia (AML) have overexpression of P-glycoprotein (Pgp+), and this has been shown to correlate quantitatively with therapeutic outcome. Since Pgp-mediated efflux of cytotoxic drugs can be inhibited by the cyclosporine analogue, PSC 833, we investigated the use of this agent with a 5-day mitoxantrone/etoposide regimen in patients over age 55 with newly diagnosed AML. Previous studies suggested a 33% incidence of grade IV/V non-hematologic toxicity with the use of mitoxantrone 10 mg/M(2) and etoposide 100 mg/M(2), each for 5 days, in this patient population. Since PSC 833 alters the pharmacokinetic excretion of MDR-related cytotoxins, this phase I dose-finding study was performed to identify doses of mitoxantrone/etoposide associated with a similar 33% incidence of grade IV/V non-hematologic toxicity, when given with PSC 833. Mitoxantrone/etoposide (M/E) doses were escalated in fixed ratio from a starting dose of M: 4 mg/M(2) and E: 40 mg/M(2), to M: 7 mg/M(2) and E: 70 mg/M(2), in successive cohorts of eight patients each. PSC 833 was well tolerated and the MTD of this M/E regimen with PSC 833 in this population was M: 6 mg/M(2) and E: 60 mg/M(2). The complete response (CR) rate for all patients was 50% (15/30) and was considerably higher for de novo than for secondary AML. These data suggest that the addition of PSC 833 to an M/E regimen for older patients with untreated AML is well tolerated but requires a reduction in M/E dosing to avoid increased toxicity.
 ...
PMID:A phase I study of induction chemotherapy for older patients with newly diagnosed acute myeloid leukemia (AML) using mitoxantrone, etoposide, and the MDR modulator PSC 833: a southwest oncology group study 9617. 1086 30

Overexpression of P-glycoprotein (P-gp) in cancer cells reduces intracellular accumulation of various anticancer drugs including anthracyclines and vinca alkaloids. This multidrug resistance (MDR) phenotype can be reversed in vitro by a number of non-cytotoxic drugs. We have identified the quinine's isomer cinchonine as a potent MDR reversing agent, both in vitro and in animal models. Here, we report an open phase I dose escalation trial in patients with refractory or relapsed malignant lymphoid diseases. Cinchonine dihydrochloride was administered by continuous i.v. infusion for 48 h and escalated over five dose levels ranging from 15 to 35 mg/kg/d. Cinchonine infusion started 24 h before i.v. doxorubicin (25 mg/m2), vinblastine (6 mg/m2), cyclophosphamide (600 mg/m2) and methylprednisolone (1 mg/kg/d) (CHVP regimen) and lasted for 24 h after chemotherapy infusion. Thirty-four patients received 87 cycles of CHVP/cinchonine. The MTD of cinchonine administered by continuous i.v. infusion was 30 mg/kg/d. Prolonged cardiac repolarization was the main dose-limiting toxicity. No ventricular arrhythmia including 'torsade de pointes' was observed. An MDR reversing activity was identified in the serum from every patient and correlated with cinchonine serum level. When infused at 30 mg/kg/d, cinchonine demonstrated a limited influence on doxorubicin pharmacokinetic. We conclude that i.v. infusion of cinchonine might be started 12 h before MDR-related chemotherapy infusion and requires continuous cardiac monitoring but no reduction of cytotoxic drug doses.
 ...
PMID:Phase I study of cinchonine, a multidrug resistance reversing agent, combined with the CHVP regimen in relapsed and refractory lymphoproliferative syndromes. 1118 97

Taxane-based chemotherapeutics are clinically available as frontline treatment regimens for cervical cancer. However, drug resistance and life-threatening toxicity impair the clinical efficacy of taxanes, so more effective and less toxic therapeutic modalities are urgently needed. Cabazitaxel has attracted increasing interest due to its potential to circumvent the drug resistance by taxanes. We previously showed that tethering docosahexaenoic acid (DHA) to cabazitaxel enabled the prodrug to self-assemble into nanoparticles in water. Despite this encouraging finding, the DHA-cabazitaxel conjugate formulation requires further optimization to enhance nanoparticle retention and tumor delivery. We here integrated this conjugate into amphiphilic poly(ethylene glycol)-block-poly(D,L-lactic acid) copolymers to assemble dCTX NPs The nanoparticle abrogated P-glycoprotein-mediated resistance in cancer cells. In a docetaxel-resistant cervical tumor xenograft-bearing mouse model, the efficacy was augmented by the nanotherapy when compared with solution-based free drugs (i.e., docetaxel and cabazitaxel). Dose intensification of dCTX NPs markedly suppressed the tumor growth in this model. Detailed studies revealed that systemic toxicity was alleviated, and MTD of dCTX NPs was at least 3 times higher than that of free cabazitaxel in animals, which may enable dose increases for clinical studies. In conclusion, the new formulation addresses essential requirements in terms of the stability, safety, and translational capacity for initiating early-phase clinical trials.
 ...
PMID:Preclinical Evaluation of a Cabazitaxel Prodrug Using Nanoparticle Delivery for the Treatment of Taxane-Resistant Malignancies. 3184 96