Inhibition of vascular endothelial growth factor-A (VEGF) signaling is a promising therapeutic approach that aims to stabilize the progression of solid malignancies by abrogating tumor-induced angiogenesis. This may be accomplished by inhibiting the kinase activity of VEGF receptor-2 (KDR), which has a key role in mediating VEGF-induced responses. The novel indole-ether quinazoline AZD2171 is a highly potent (IC50 < 1 nmol/L) ATP-competitive inhibitor of recombinant KDR tyrosine kinase in vitro. Concordant with this activity, in human umbilical vein endothelial cells, AZD2171 inhibited VEGF-stimulated proliferation and KDR phosphorylation with IC50 values of 0.4 and 0.5 nmol/L, respectively. In a fibroblast/endothelial cell coculture model of vessel sprouting, AZD2171 also reduced vessel area, length, and branching at subnanomolar concentrations. Once-daily oral administration of AZD2171 ablated experimental (VEGF-induced) angiogenesis in vivo and inhibited endochondral ossification in bone or corpora luteal development in ovary; physiologic processes that are highly dependent upon neovascularization. The growth of established human tumor xenografts (colon, lung, prostate, breast, and ovary) in athymic mice was inhibited dose-dependently by AZD2171, with chronic administration of 1.5 mg per kg per day producing statistically significant inhibition in all models. A histologic analysis of Calu-6 lung tumors treated with AZD2171 revealed a reduction in microvessel density within 52 hours that became progressively greater with the duration of treatment. These changes are indicative of vascular regression within tumors. Collectively, the data obtained with AZD2171 are consistent with potent inhibition of VEGF signaling, angiogenesis, neovascular survival, and tumor growth. AZD2171 is being developed clinically as a once-daily oral therapy for the treatment of cancer.
The effects of L-NG-nitro arginine (L-NOARG) on a-chymotrypsin-resistant, non-adrenergic, noncholinergic (NANC) relaxations of guinea-pig tracheal smooth muscle have been examined. L-NOARG (1-100pM), but not D-NOARG (100pM), inhibited the NANC relaxations in a concentration-related manner. The effects of L-NOARG were partially reversed by L-arginine but not D-arginine. L-NOARG was without effect on acetylcholine-induced contractile responses of the trachea or on relaxations produced by vasoactive intestinal peptide, sodium nitroprusside or isoprenaline. These results suggest that an endogenous nitrate may contribute to NANC relaxations of tracheal smooth muscle.Introduction In many species, including man and guinea-pig, electrically induced relaxations of tracheal smooth muscle have a non-adrenergic, non-cholinergic (NANC) component (Barnes, 1986). The identity of the neurotransmitter which mediates this effect is unknown and may vary with the species studied. In the guinea-pig, vasoactive intestinal peptide (VIP) and peptide histidine isoleucine (PHI) are strong candidates for at least part of this NANC relaxant response. Ellis &
Purpose: Vascular endothelial growth factor (VEGF) plays a key role in tumor angiogenesis and acts as a radiation survival factor for endothelial cells. ZD6474 (N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]-quinazolin-4-amine) is a potent VEGF receptor 2 (KDR) tyrosine kinase inhibitor (TKI) that has additional activity versus the epidermal growth factor receptor. This study was designed to determine the efficacy of combining ZD6474 and radiotherapy in vivo.Experimental Design: The Calu-6 (non-small-cell lung cancer) tumor model was selected because it was found to be unresponsive to treatment with a selective epidermal growth factor receptor TKI but responds significantly to treatment with selective VEGF receptor TKIs. Tumor-bearing mice received either vehicle or ZD6474 (50 mg/kg, by mouth, once daily) for the duration of the experiment, with or without radiotherapy (3 ؋ 2 Gy, days 1-3). Two combination schedules were examined: (a) ZD6474 given before each dose of radiation (concurrent schedule); and (b) ZD6474 given 30 minutes after the last dose of radiotherapy (sequential schedule).Results: The growth delay induced using the concurrent schedule was greater than that induced by ZD6474 or radiation treatment alone (22 ؎ 1 versus 9 ؎ 1 and 17 ؎ 2 days, respectively; P ؍ 0.03 versus radiation alone). When administered sequentially, the growth delay was markedly enhanced (36 ؎ 1 days; P < 0.001 versus radiation alone or the concurrent schedule). Intravenous administration of Hoechst 33342 showed a trend toward reduced tumor perfusion after ZD6474 treatment, and a pairwise comparison (versus control) was significant after three doses of ZD6474 (P ؍ 0.05 by one-tailed t test). Thus, impaired reoxygenation between fractions in the concurrent protocol may be the causal basis for the schedule dependency of the radiopotentiation observed.Conclusions: ZD6474 may be a successful adjuvant to clinical radiotherapy, and scheduling of the treatments could be important to ensure optimal efficacy.
Continued androgen receptor (AR) expression and signaling is a key driver in castration-resistant prostate cancer (CRPC) after classical androgen ablation therapies have failed, and therefore remains a target for the treatment of progressive disease. Here, we describe the biological characterization of AZD3514, an orally bioavailable drug that inhibits androgen-dependent and -independent AR signaling. AZD3514 modulates AR signaling through two distinct mechanisms, an inhibition of ligand-driven nuclear translocation of AR and a downregulation of receptor levels, both of which were observed in vitro and in vivo. AZD3514 inhibited testosterone-driven seminal vesicle development in juvenile male rats and the growth of androgen-dependent Dunning R3327H prostate tumors in adult rats. Furthermore, this class of compound showed antitumor activity in the HID28 mouse model of CRPC in vivo. AZD3514 is currently in phase I clinical evaluation.
Cediranib is a potent inhibitor of the VEGF receptor (VEGFR)-2 and VEGFR-3 tyrosine kinases. This study assessed the activity of cediranib against the VEGFR-1 tyrosine kinase and the platelet-derived growth factor receptor (PDGFR)-associated kinases c-Kit, PDGFR-a, and PDGFR-b. Cediranib inhibited VEGF-A-stimulated VEGFR-1 activation in AG1-G1-Flt1 cells (IC 50 ¼ 1.2 nmol/L). VEGF-A induced greatest phosphorylation of VEGFR-1 at tyrosine residues Y1048 and Y1053; this was reversed by cediranib. Potency against VEGFR-1 was comparable with that previously observed versus VEGFR-2 and VEGFR-3. Cediranib also showed significant activity against wild-type c-Kit in cellular phosphorylation assays (IC 50 ¼ 1-3 nmol/L) and in a stem cell factor-induced proliferation assay (IC 50 ¼ 13 nmol/L). Furthermore, phosphorylation of wildtype c-Kit in NCI-H526 tumor xenografts was reduced markedly following oral administration of cediranib (!1.5 mg/kg/d) to tumor-bearing nude mice. The activity of cediranib against PDGFR-b and PDGFR-a was studied in tumor cell lines, vascular smooth muscle cells (VSMC), and a fibroblast line using PDGF-AA and PDGF-BB ligands. Both receptor phosphorylation (IC 50 ¼ 12-32 nmol/L) and PDGF-BB-stimulated cellular proliferation (IC 50 ¼ 32 nmol/L in human VSMCs; 64 nmol/L in osteosarcoma cells) were inhibited. In vivo, ligand-induced PDGFR-b phosphorylation in murine lung tissue was inhibited by 55% following treatment with cediranib at 6 mg/kg but not at 3 mg/kg or less. In contrast, in C6 rat glial tumor xenografts in mice, ligand-induced phosphorylation of both PDGFR-a and PDGFR-b was reduced by 46% to 61% with 0.75 mg/kg cediranib. Additional selectivity was showed versus Flt-3, CSF-1R, EGFR, FGFR1, and FGFR4. Collectively, these data indicate that cediranib is a potent pan-VEGFR kinase inhibitor with similar activity against c-Kit but is significantly less potent than PDGFR-a and PDGFR-b. Mol Cancer Ther; 10(5); 861-73. Ó2011 AACR.
1 The effect of five S-nitrosothiols, and of the stereoisomers of N0-hydroxy-arginine (HOARG), were investigated on the mouse anococcygeus. 2 All five S-nitrosothiols produced concentration-related (0.1-100IM) relaxations of carbachol (50 LM)-induced tone; the order of potency was S-nitroso-L-cysteine (CYSNO)> S-nitroso-N-acetyl-D,Lpenicillamine (SNAP)>S-nitrosoglutathione (GSNO)> S-nitrosocoenzyme A (CoASNO)> S-nitroso-N-acetyl-L-cysteine (NACNO). The relaxations were unaffected by the nitric oxide synthase (NOS) inhibitor, L-NG-nitro-arginine (10 JIM) (L-NOARG).3 Cold-storage of the tissue for 72 h resulted in loss of sympathetic and non-adrenergic, noncholinergic (NANC) nerve function. NOS activity in the tissue was reduced by 97%. Despite this, relaxations induced by the S-nitrosothiols were unaffected. 4 Haemoglobin (50 jM) attenuated relaxations induced by NO and the S-nitrosothiols, although responses to 3-isobutyl-1-methyl-xanthine were unaffected. N-methyl-hydroxylamine (2 mM) which has been shown previously to produce selective inhibition of NANC and nitrovasodilator responses in this tissue, also reduced responses to all S-nitrosothiols.5 Hydroquinone (100 gM) greatly reduced relaxations to CYSNO (by 88%) but had no effect on those to SNAP, GSNO, CoASNO or NACNO. Since hydroquinone does not reduce responses to NANC stimulation, CYSNO is unlikely to be the NANC transmitter. 6 L-HOARG by itself (up to 100 piM) had no significant effect on carbachol-induced tone or on NANC (10 Hz; 10 s train every 100 s) relaxations. However, it produced reversal of the inhibitory effects of L-NOARG (10;pM), being only slightly less potent than L-arginine. D-HOARG was without effect. L-HOARG had no effect on relaxations induced by 1.51iM NO. 7 The results show that S-nitrosothiols are potent relaxants of the mouse anococcygeus; they act directly on the smooth muscle with a mechanism similar to NO and other nitrovasodilators. In addition, the results are consistent with L-HOARG being an intermediate in the biosynthesis of NO from L-arginine, although there is no evidence for it acting to stabilize NO extracellularly.
1. The possibility of an interaction between the motor sympathetic and inhibitory non-adrenergic, non-cholinergic (NANC) nerves in the rat anococcygeus was investigated using L-NG-nitro-arginine (L-NOARG), an inhibitor of L-arginine: NO synthase. 2. L-NOARG (50 microM) increased contractions induced by field stimulation (20 s trains; 0.5-40 Hz); overall, the frequency-response curve was displaced six-fold to the left. D-NOARG (50 microM) was without effect. 3. The potentiation produced by L-NOARG was reversed by 200 microM L-, but not D-, arginine. 4. L-NOARG had no effect on contractions induced by exogenous noradrenaline (NA) or on field stimulation-induced overflow of tritium from muscles previously loaded with [3H]-NA. 5. It is concluded that the endogenous nitrate NANC transmitter does not influence release of NA from the sympathetic nerves and the potentiation of contractions induced by field stimulation in the presence of L-NOARG most probably results from removal of the opposing relaxing influence of concomitantly released NANC transmitter.
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