BMS-754807 is a potent and reversible inhibitor of the insulin-like growth factor 1 receptor/insulin receptor family kinases (Ki, <2 nmol/L). It is currently in phase I development for the treatment of a variety of human cancers. BMS-754807 effectively inhibits the growth of a broad range of human tumor types in vitro, including mesenchymal (Ewing's, rhabdomyosarcoma, neuroblastoma, and liposarcoma), epithelial (breast, lung, pancreatic, colon, gastric), and hematopoietic (multiple myeloma and leukemia) tumor cell lines (IC 50 , 5-365 nmol/L); the compound caused apoptosis in a human rhabdomyosarcoma cell line, Rh41, as shown by an accumulation of the sub-G 1 fraction, as well as by an increase in poly ADP ribose polymerase and Caspase 3 cleavage. BMS-754807 is active in vivo in multiple (epithelial, mesenchymal, and hematopoietic) xenograft tumor models with tumor growth inhibition ranging from 53% to 115% and at a minimum effective dose of as low as 6.25 mg/kg dosed orally daily. Combination studies with BMS-754807 have been done on multiple human tumor cell types and showed in vitro synergies (combination index, <1.0) when combined with cytotoxic, hormonal, and targeted agents. The combination of cetuximab and BMS-754807 in vivo, at multiple dose levels, resulted in improved clinical outcome over single agent treatment. These data show that BMS-754807 is an efficacious, orally active growth factor 1 receptor/insulin receptor family-targeted kinase inhibitor that may act in combination with a wide array of established anticancer agents.
mTOR (mammalian target of rapamycin) is a protein kinase that regulates cell cycle progression and cell growth. Rapamycin is a highly specific inhibitor of mTOR in clinical trials for the treatment of breast and other cancers. mTOR signaling was reported to require phosphatidic acid (PA), the metabolic product of phospholipase D (PLD). PLD, like mTOR, has been implicated in survival signaling and the regulation of cell cycle progression. PLD activity is frequently elevated in breast cancer. We have investigated the effect of rapamycin on breast cancer cell lines with different levels of PLD activity. MCF-7 cells, with relatively low levels of PLD activity, were highly sensitive to the growth-arresting effects of rapamycin, whereas MDA-MB-231 cells, with a 10-fold higher PLD activity than MCF-7 cells, were highly resistant to rapamycin. Elevating PLD activity in MCF-7 cells led to rapamycin resistance; and inhibition of PLD activity in MDA-MB-231 cells increased rapamycin sensitivity. Elevated PLD activity in MCF-7 cells also caused rapamycin resistance for S6 kinase phosphorylation and serum-induced Myc expression. These data implicate mTOR as a critical target for survival signals generated by PLD and suggest that PLD levels in breast cancer could be a valuable indicator of the likely efficacy of rapamycin treatment.
The novel tyrosine kinase inhibitor dasatinib (Sprycel; BMS-354825) is approved for use in imatinib (Gleevec; STI 571)-resistant or -intolerant chronic myelogenous leukemia and may be useful for other tumors in the central nervous system (CNS). The objective of this study was to investigate the role of Pglycoprotein (P-gp) and breast cancer resistance protein (BCRP) in modulating the CNS penetration of dasatinib. Results from the in vitro studies indicate that cellular delivery of dasatinib is significantly limited by active efflux due to both P-gp and BCRP. Permeability studies indicated greater permeability in the basolateral-to-apical direction than in the apical-to-basolateral direction due to active efflux by P-gp or BCRP. Selective inhibitors of P-gp and BCRP, such as (R)-4-((1aR,6R,10bS)-1,2-difluoro-1,1a,6,10b-tetrahydrodibenzo-(a,e)cyclopropa(c) cycloheptan-6-yl)-␣-((5-quinoloyloxy)methyl)-1-piperazineethanol, trihydrochloride (zosuquidar; LY335979) and 3-(6-isobutyl-9-methoxy-1,4-dioxo-1,2,3,4,6,7,12,12␣-octahydropyrazino1Ј,2Ј: 1,6pryrido3,4-bindol-3-yl)-propionic acid tert-butyl ester (Ko143), were able to restore the intracellular accumulation and abolish the directionality in net flux of dasatinib. In vivo brain distribution studies showed that the CNS distribution of dasatinib is limited, with the brain-to-plasma concentration ratios less than 0.12 in wild-type mice, which increased approximately 8-fold in Mdr1a/ b(Ϫ/Ϫ) Bcrp1(Ϫ/Ϫ) mice. Dasatinib brain distribution was significantly increased in Mdr1a/b(Ϫ/Ϫ) mice and when wild-type mice were pretreated with LY335979. Simultaneous inhibition of P-gp and BCRP by elacridar [N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide] (GF120918) resulted in a 5-fold increase in brain concentration. These in vitro and in vivo studies demonstrate that dasatinib is a substrate for the important efflux transporters p-glycoprotein and BCRP. These transport systems play a significant role in limiting the CNS delivery of dasatinib and may have direct implications in the treatment of primary and metastatic brain tumors.Chronic myelogenous leukemia (CML) accounts for 15 to 20% of all cases of adult leukemia in western populations (Quintá s-Cardama et al., 2007). Imatinib (Gleevec; STI 571) is a first-generation tyrosine kinase inhibitor (TKI) that was approved for use in the treatment of CML and gastrointestinal stromal tumor (Druker, 2003). Imatinib inhibits the BCR-ABL, c-kit, platelet-derived growth factor, and the Ablrelated gene tyrosine kinases . CNS involvement is a common complication seen in CML, and most patients with CML and Ph ϩ acute lymphoblastic leukemia (Ph ϩ ALL) develop extramedullary involvement during the course of their disease. CNS failure has been reported in approximately 20% of imatinib-treated patients with CML or Ph ϩ ALL (Leis et al., 2004). CNS relapses were observed in patients despite a complete hematological response (Leis et Article, publication date, and c...
17alpha-Ethinylestradiol (EE) is widely used as the estrogenic component of oral contraceptives (OC). In vitro and in vivo metabolism studies indicate that EE is extensively metabolised, primarily via intestinal sulfation and hepatic oxidation, glucuronidation and sulfation. Cytochrome P450 (CYP)3A4-mediated EE 2-hydroxylation is the major pathway of oxidative metabolism of EE. For some time it has been known that inducers of drug-metabolising enzymes (such as the CYP3A4 inducer rifampicin [rifampin]) can lead to breakthrough bleeding and contraceptive failure. Conversely, inhibitors of drug-metabolising enzymes can give rise to elevated EE plasma concentrations and increased risks of vascular disease and hypertension. In vitro studies have also shown that EE inhibits a number of human CYP enzymes, such as CYP2C19, CYP3A4 and CYP2B6. Consequently, there are numerous reports in the literature describing EE-containing OC formulations as perpetrators of pharmacokinetic drug interactions. Because EE may participate in multiple pharmacokinetic drug interactions as either a victim or perpetrator, pharmaceutical companies routinely conduct clinical drug interaction studies with EE-containing OCs when evaluating new chemical entities in development. It is therefore critical to understand the mechanisms underlying these drug interactions. Such an understanding can enable the interpretation of clinical data and lead to a greater appreciation of the profile of the drug by physicians, clinicians and regulators. This article summarises what is known of the drug-metabolising enzymes and transporters governing the metabolism, disposition and excretion of EE. An effort is made to relate this information to known clinical drug-drug interactions. The inhibition and induction of drug-metabolising enzymes by EE is also reviewed.
MDA-MB-231 human breast cancer cells belong to a highly invasive metastatic cell line that depends on phospholipase D (PLD) activity for survival when deprived of serum growth factors. In response to the stress of serum withdrawal, there is a rapid and dramatic increase in PLD activity. Concomitant with increased PLD activity, there was an increase in the ability of MDA-MB-231 cells to both migrate and invade Matrigel TM . The ability of MDA-MB-231 cells to both migrate and invade Matrigel TM was dependent on both PLD and mTOR, a downstream target of PLD signals. Serum withdrawal also led to a PLD-dependent increase in the expression of the stress factor, hypoxia-inducible factor-1␣. These data reveal that PLD survival signals not only prevent apoptosis but also stimulate cell migration and invasion, linking the ability to suppress apoptosis with the ability to metastasize.The conversion of a normal cell to a malignant cancer cell involves multiple genetic alterations that overcome the many protections built into cells that prevent unwanted proliferation (1). Perhaps the most crucial step in progression to malignancy is gaining the ability to migrate or metastasize to distant sites where the growth of multiple tumors ultimately causes the lethal consequences of the cancer. Although there are several cellular properties that correlate with increased metastatic potential, such as increased protease secretion (2), there has never been a clear genetic event that confers metastatic capability. However, it has been suggested that mutations occurring at early stages of tumorigenesis that confer a proliferative advantage may also contribute to the ability to metastasize at later stages of tumor progression (3).Among the obstacles to be overcome in a developing tumor are default apoptotic programs that cause cells with faulty division signals to undergo apoptosis (1). A cell must generate "survival signals" to suppress these apoptotic programs (4 -6). Interestingly, signals that have been shown to suppress apoptosis have also been linked to cell migration, a hallmark of the metastatic phenotype. Both phosphatidylinositol 3-kinase and phospholipase D (PLD), 2 which provide survival signals in human cancer cells (7-9), have also been linked with cellular processes that contribute to cell migration (8,10). This correlation between survival and cell migration suggests that generating a survival signal early in tumorigenesis could also endow the cell with the ability to migrate. This raises the question as to how the migration would be triggered. One possibility is that although a primary tumor mass is forming, survival signals are selected for in cells deprived of blood serum to suppress the apoptosis that would occur in an unvascularized tumor mass. If the survival response of cells also includes increased cell migration, then in addition to suppression of apoptosis, the response would also include migration to sites where growth factors and nutrition could be obtained.We recently described a survival signal in the highly m...
p53 is the most commonly mutated gene in human cancer. Although the loss of tumor suppressor functions for p53 in tumorigenesis is well characterized, gain-of-function p53 mutations observed in most cancers are not as widely appreciated. The human breast cancer cell line MDA-MB-231, which has high levels of a mutant p53, has high levels of phospholipase D (PLD) activity, which provides a survival signal in these cells when deprived of serum growth factors. We report here that the mutant p53 in MDA-MB-231 cells is stabilized by the elevated PLD activity in these cells. Surprisingly, the survival of MDA-MB-231 cells deprived of serum was dependent on the mutant p53. These data indicate that a mutant p53, stabilized by elevated PLD activity, can contribute to the suppression of apoptosis in a human breast cancer cell line and suggest a rationale for the selection of p53 mutations early in tumorigenesis to suppress apoptosis in an emerging tumor.
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