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)

There are two broad categories of drug resistance encountered during cancer chemotherapy, i.e. intrinsic and acquired. They are observed in virtually every type of tumor with every known anticancer chemotherapeutic drug. As such there is an urgent need to develop innovative approaches of preventing or reversing these types of resistance. One strategy to do so is to develop completely new drugs which may be resistance free, such as direct acting angiogenesis inhibitors (T. Boehm, J. Folkman, T. Browder, M.S. O'Reilly, Antiangiogenic therapy of experimental cancer does not induce acquired drug resistance, Nature 390 (1997) 404-407; R.S. Kerbel, Inhibition of tumor angiogenesis as a strategy to circumvent acquired resistance to anti-cancer therapeutic agents, BioEssays 13 (1991) 31-36; R.S. Kerbel, A cancer therapy resistant to resistance, Nature 390 (1997) 335-336). Another is to devise methods which will improve significantly the effectiveness of those conventional drugs already in use, such as adriamycin, cyclophosphamide and taxol. We have directed efforts towards the latter. They depend on the discovery of a new class of chemosensitizers which act as antiadhesive agents rendering solid tumors more susceptible to such conventional cytotoxic therapeutic drugs. Examples of this concept are illustrated with bovine testicular hyaluronidase and a mouse mammary tumor called EMT-6. When this enzyme preparation is used to treat intact multicellular spheroids of the EMT-6 tumor, the spheroids are substantially disaggregated. Dispersed spheroids are more susceptible to the cytotoxic effects of cyclophosphamide than intact spheroids. Moreover, this antiadhesive chemosensitizing effect can actually be reproduced in BALB/c mice when EMT-6 cells are grown intraperitoneally as an ascites tumor (consisting mostly of multicellular aggregates) and the mice are given injections of hyaluronidase and cyclophosphamide. In a similar fashion, the indifference of P-glycoprotein-positive multidrug-resistant EMT-6 spheroids to the P-glycoprotein reversal agent PSC-833 (a cyclosporin A analogue) can be reversed by disaggregation of the intact spheroids by hyaluronidase. This renders the treated cells highly sensitive to a combination of adriamycin and PSC-833 in a manner similar to the striking chemosensitization effects commonly observed in monolayer culture systems. Thus, hyaluronidase has the potential to reverse forms of both intrinsic and acquired drug resistance in solid tumors, such as EMT-6, which are sensitive to its antiadhesive effects.
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PMID:Reversal of intrinsic and acquired forms of drug resistance by hyaluronidase treatment of solid tumors. 983 18

Heterocyclic phenazinecarboxamides were prepared by condensation of aminoheterocycles and 2-halo-3-nitrobenzoic acids, followed by reductive ring closure and amidation. They showed similar inhibition of paired cell lines that underexpressed topo II or overexpressed P-glycoprotein, indicating a non topo II mechanism of cytotoxicity and indifference to P-glycoprotein mediated multidrug resistance. Compounds with a fused five-membered heterocyclic ring were generally less potent than the pyrido[4,3-a]phenazines. A 4-methoxypyrido[4,3-a]phenazine (IC(50)s 2.5-26 nM) gave modest (ca. 5 day) growth delays in H69/P xenografts with oral dosing.
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PMID:Structure-activity relationships for pyrido-, imidazo-, pyrazolo-, pyrazino-, and pyrrolophenazinecarboxamides as topoisomerase-targeted anticancer agents. 1180 25

Objective To observe the changes of expression of P-glycoprotein (PGP) in the brain of pentylenetetrazole (PTZ)-kindled epileptic mice after 2-chloride adenosine (2-CAdo) stimulation. Methods The C57BL/6 mice (n=40) were randomly divided into three groups: control group (n=8), PTZ group (n=16) and 2-CAdo group (n=16). The epileptic model was established by intraperitoneal injection of PTZ [30 mg/(kg.d)]. The control group were given the same amount of normal saline. The seizures were observed during PTZ kindling (kindling rate, latency time, start time and durations of seizures). After kindled, the 2-CAdo group was continuously injected with 2-CAdo [0.6 mg/(kg.d)] for 2 weeks. The other two groups were injected with normal saline instead. Then, all the mice of these three groups were sacrificed. HE staining was adopted to observe the histopathological changes of cerebral cortex and hippocampus of the mice, and the expression of PGP was detected by immunohistochemistry and Western blotting. Results At the time of seizures, the mice showed whole body tremor, hair erection, apathy, loss of appetite, cage offense and other abnormalities. HE staining showed that the damage of cerebral cortex and hippocampus of the 2-CAdo group was less than that of the PTZ group. Immunohistochemistry and Western blotting showed that the expression of PGP in the cerebral cortex of the 2-CAdo group was significantly lower than that in the control and PTZ groups. In the hippocampus, the expression of PGP in the 2-CAdo and PTZ groups was significantly higher than that in the control group, especially highest in the 2-CAdo group. Conclusion The 2-CAdo can reduce the damage of brain tissue, upregulate the expression of PGP in the hippocampus, and downregulate the expression of PGP in the cerebral cortex.
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PMID:[The 2-chloride adenosine alleviates the damage of brain tissues in pentylenetetrazole-kindled epileptic mice by regulating P-glycoprotein expression]. 2839 20