Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.3.1 (alkaline phosphatase)
 47,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The antineoplastic properties of suramin, a polyanionic agent with demonstrated antigrowth factor activity, are under evaluation in vitro, in vivo, and in clinical trials. Suramin has been shown to have antitumor activity in patients with advanced, hormone refractory prostate cancer. During these trials, significant resolution of osseous pain was observed in nearly three quarters of the patients treated with suramin. To evaluate the effect of suramin on bone cells, we studied the effect of suramin on bone resorption in a neonatal mouse calvarial assay. Suramin inhibited bone-resorbing activity in a dose-related fashion and had an additive effect with calcitonin. Calvaria pretreated with suramin had less bone-resorbing activity, fewer attached osteoblasts, and less medium alkaline phosphatase activity than control calvaria. Suramin also inhibited osteoclastic release of tritiated proline from labeled bone in a dose-dependent fashion. The effect of metastatic prostate carcinoma on bone is incompletely understood, but may be moderated by tumor-produced factors and/or cytokines. The effects of several such agents, therefore, were examined in combination with suramin. Bone resorption induced by PTH, epidermal growth factor, tumor necrosis factor, and a tumor-produced factor, PTH related-protein, was blocked by suramin. The ability of suramin to inhibit the bone-resorbing effects of several cytokines suggests that its mechanism may involve direct action on bone metabolism. Autoradiography performed on calvaria treated with labeled suramin demonstrated heavy deposition of suramin on the outer surface of the matrix, adjacent to osteoblasts and osteoclasts lining the outer table, suggesting that bone cells may be subject to high local concentrations of the drug, in keeping with this hypothesis.
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PMID:Suramin inhibits bone resorption and reduces osteoblast number in a neonatal mouse calvarial bone resorption assay. 142 26

Yondelis (trabectedin, ET-743) is a novel marine-derived anticancer compound found in the ascidian Ecteinascidia turbinata. It is currently under phase II/III development in breast cancer, hormone refractory prostate cancer, sarcomas and ovarian cancer. Activity in breast cancer experimental models has been reported, and preliminary evidence of activity in this setting during the phase I programme has also been observed. The present study assessed the activity and feasibility of trabectedin in women with advanced breast cancer previously treated with conventional therapies. Patients with advanced disease previously treated with at least one but not more than two regimens that included taxanes or anthracyclines as palliative therapy were eligible. Trabectedin 1.5 mg m(-2) was administered as a 24-h continuous infusion every 3 weeks. Patients were kept on therapy until disease progression, unacceptable toxicity or patient refusal. Twenty-seven patients were included between April 1999 and September 2000. Their median age was 54 years (range: 36-67) and 63% of them had two metastatic sites. Twenty-two patients were performance status 1. All patients had previously received anthracyclines, and 23 out of 27 patients had received taxanes. Of 21 patients with measurable disease, three confirmed partial responses, one unconfirmed partial response and two minor responses (49 and 32% tumour shrinkage) were observed; six patients had stable disease. Median survival was 10 months (95% confidence interval: 4.88-15.18). Transient and noncumulative transaminitis was observed in most of the patients. The pharmacokinetic profile of trabectedin in this patient's population is in line with the overall data available with this schedule. The policy of dose adjustments based on the intercycle peaks of bilirubin and alkaline phosphatase appears to have a positive impact in the therapeutic index of trabectedin. Trabectedin can induce response and tumour control in previously treated advanced breast cancer, with manageable toxicity, thus warranting further development as a single agent or in combination regimens.
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PMID:A phase II study of Yondelis (trabectedin, ET-743) as a 24-h continuous intravenous infusion in pretreated advanced breast cancer. 1673 24

The aim of the present study was to compare a novel marker for high bone turnover with two routine markers for screening in prostate cancer patients. The markers were evaluated in two studies: (a) a cross-sectional study of 170 prostate cancer patients with local disease stratified by +/-lymph node metastases (N 0, N1) compared with controls and (b) a longitudinal study of 40 hormone refractory prostate cancer patients stratified by skeletal involvement and followed during docetaxel (+/-BM) and zoledronate (+BM) treatment. Presence or absence of bone metastases (BM) was assessed by imaging techniques (magnetic resonance imaging or X-ray) and technetium-99m scintigraphy. The serum or urinary levels of alpha C-telopeptide of collagen type I (alphaalphaCTX), prostate-specific antigen (PSA), and total alkaline phosphatase (tALP) were assessed. PSA was elevated in both N 0 and N1 patients compared with controls, whereas alphaalphaCTX was elevated only in N1 patients. tALP exhibited no difference in any of the groups. In the treatment study, PSA decreased with treatment in both the -BM and +BM groups compared with baseline values, showing similar effect of docetaxel or docetaxel/zoledronate treatment on this marker. On the contrary, alphaalphaCTX and tALP did not decrease with docetaxel treatment in the -BM group compared with baseline, whereas it decreased significantly with docetaxel/zoledronate treatment in the +BM group, already after 1 month of treatment for alphaalphaCTX. Results suggest that alphaalphaCTX is superior to PSA and tALP for identifying patients having a high risk of metastatic disease and for monitoring skeletal progression in +BM prostate cancer patients during treatment.
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PMID:Biochemical markers for monitoring response to therapy: evidence for higher bone specificity by a novel marker compared with routine markers. 1848 50

The alpha emitter Radium-223 ((22)3Ra-Cl2) is a bone-seeking radionuclide studied as a new treatment for patients with bone metastases from hormone refractory prostate cancer. More than 1,000 patients have been included in clinical phase I-III tests showing significant reduction in alkaline phosphatase- and PSA level and prolonged survival. Adverse events are usually mild to moderate and comprise gastrointestinal and myelotoxic symptoms. Intravenously administered (22)3Ra-Cl2 (half-life 11.4 days) will likely be given every four weeks for six treatments to out-patients.
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PMID:[Radium-223 treatment of bone metastases from castration-resistant prostate cancer]. 2529 32

Prostate cancer remains the second leading cause of cancer death in men due to inefficiency of androgen deprivation therapy or androgen blockade. Endothelins (ETs) and the two endothelin receptor family members A and B (ETA and ETB) are known to play important roles in the progression of many malignancies, including prostate cancer. However, phase III clinical studies did not reach a unanimous conclusion regarding ETA receptor antagonists in prostate cancer treatment. Here, we provide a meta-analysis of clinical studies using ETA receptor antagonists to treat prostate cancer, especially the hormone refractory prostate cancer (HRPC). Data were extracted from nine studies that used Zibotentan or Atrasentan, two selective ETA receptor antagonists, to treat prostate cancer and meet the selection criteria. The results indicated that the overall survival (OS) and the progression-free survival (PFS) of patients treated with Zibotentan did not show significant difference with the patients treated with placebo (pooled hazard ratio (HR) for OS, 0.86, 95% CI 0.70-1.06; pooled HR for PFS, 0.98, 95% CI 0.91-1.06). No statistically significant difference was detected either as to the OS and PFS of patients between the Atrasentan treated group and the group treated with placebo (pooled HR for OS, 0.99, 95% CI 0.90-1.08; pooled HR for PFS, 0.94, 95% CI 0.86-1.02). Notably, the level of prostate-specific antigen (PSA) and the incidence of bone pain were significantly lower in the Atrasentan treated patients compared to the controls (pooled HR for time of PSA progression, 0.87, 95% CI 0.78-0.97; and pooled relative risk (RR) for bone pain, 0.68, 95% CI 0.48-0.97). In addition, increasing of PSA and bone alkaline phosphatase (BALP) were significantly delayed with Atrasentan treatment (P<0.05). Together, these data suggest that Atrasentan has an effect on cancer-related bone pain and skeletal-events in patients with prostate cancer.
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PMID:Endothelin-A receptor antagonists in prostate cancer treatment-a meta-analysis. 2606 37