Suppression of Prostate Cancer Induced Bone Remodeling by The Endothelin Receptor a Antagonist Atrasentan

Nelson, Joel B.; Nabulsi, Azmi A.; Vogelzang, Nicholas J.; Breul, Jürgen; Zonnenberg, Bernard A.; Daliani, Danai; Schulman, Claude; Carducci, Michael A.

doi:10.1097/01.ju.0000042162.08938.27

Cited by 129 publications

(70 citation statements)

References 16 publications

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“…The agent delayed time to progression and decreased markers of tumour burden. Of particular interest, atrasentan decreased markers of bone remodelling, which were elevated in patients with prostate cancer (Nelson et al 2003b). This result supports the importance of the vicious cycle model, in which targeting one step serves to suppress all parts of the cycle.…”

Section: Etar Antagonistssupporting

confidence: 68%

“…The ET receptor antagonist blocks the activation of osteoblasts by tumour-produced ET-1. It also decreases osteoclastic bone resorption, as indicated by decreases in markers of resorption seen in patient trials (Nelson et al 2003b). Conversely, bisphosphonates effectively reduce skeletal-related events (SREs) in prostate cancer (Saad et al 2002).…”

Section: Osteoblastic Metastasismentioning

confidence: 99%

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Hypercalcaemia of malignancy and basic research on mechanisms responsible for osteolytic and osteoblastic metastasis to bone

Clines

Guise²

2005

Endocr Relat Cancer

229

211

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Calcium homeostasis is a tightly regulated process involving the co-ordinated efforts of the skeleton, kidney, parathyroid glands and intestine. Neoplasms can alter this homeostasis indirectly through the production of endocrine factors resulting in humoral hypercalcaemia of malignancy. Relatively common with breast and lung cancer, this paraneoplastic condition is most often due to tumour production of parathyroid hormone-related protein and ensuing increased osteoclastic bone resorption. Although control of hypercalcaemia is generally successful, the development of this complication is associated with a poor prognosis. The metastasis of tumour cells to bone represents another skeletal complication of malignancy. As explained in the 'seed and soil' hypothesis, bone represents a fertile ground for cancer cells to flourish. The molecular mechanisms of this mutually beneficial relationship between bone and cancer cells are beginning to be understood. In the case of osteolytic bone disease, tumour-produced parathyroid hormone-related protein stimulates osteoclasts that in turn secrete tumour-activating transforming growth factor-b that further stimulates local cancer cells. This 'vicious cycle' of bone metastases represents reciprocal bone/ cancer cellular signals that likely modulate osteoblastic bone metastatic lesions as well. The development of targeted therapies to either block initial cancer cell chemotaxis, invasion and adhesion or to break the 'vicious cycle' is dependent on a more complete understanding of bone metastases. Although bisphosphonates delay progression of skeletal metastases, it is clear that more effective therapies are needed. Cancer-associated bone morbidity remains a major public health problem, and to improve therapy and prevention it is important to understand the pathophysiology of the effects of cancer on bone. This review will detail scientific advances regarding this area.

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Section: Etar Antagonistssupporting

confidence: 68%

Section: Osteoblastic Metastasismentioning

confidence: 99%

Hypercalcaemia of malignancy and basic research on mechanisms responsible for osteolytic and osteoblastic metastasis to bone

Clines

Guise²

2005

Endocr Relat Cancer

229

211

View full text Add to dashboard Cite

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“…a factor in tumor growth. Randomized placebo-controlled Phase II studies demonstrated a consistent ability of atrasentan to attenuate the increase in markers of prostate cancer progression such as prostate-specific antigen, alkaline phosphatase, Ntelopeptides, C-telopeptides, deoxypyridinoline, and lactate dehydrogenase (22)(23)(24). Phase III trials comparing atrasentan to placebo are nearing completion.…”

Section: Discussionmentioning

confidence: 99%

Dose-Ranging Study of the Safety and Pharmacokinetics of Atrasentan in Patients with Refractory Malignancies

Ryan

Vogelzang

Vokes

et al. 2004

Clinical Cancer Research

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Purpose: Atrasentan is an orally bioavailable selective antagonist of the endothelin receptor ET A . Due to the potential activity of this agent against prostate cancer, the majority of subjects enrolled in prior studies had been male. This Phase I study sought to determine the toxicity and pharmacokinetics of daily atrasentan in a population of both female and male subjects with advanced malignancies.Experimental Design: Patients with refractory malignancies received atrasentan once daily at doses ranging from 5 mg to 75 mg. At least 3 subjects were treated at each dose level before enrollment began at the next higher dose level. Enrollment for specific dose levels was expanded if any subject experienced serious drug-related toxicity. Plasma concentration profiles for atrasentan were determined after dosing on days 1 and 28.Results: Thirty-five patients received atrasentan at doses from 5 mg to 75 mg. The most frequent drug-related adverse events were headache (60%), rhinitis (49%), and peripheral edema (31%). These toxicities were mild to moderate in severity and reversible on cessation of treatment. Dose escalation was stopped at the 75-mg dose level due to the occurrence of three severe adverse events (2 hyponatremia and 1 hypotension). Atrasentan was rapidly absorbed after oral administration; mean time to maximum observed concentration ranged from 0.3 to 1.7 h. Terminal elimination half-life averaged 26 h. No significant difference between sexes was found in any atrasentan pharmacokinetic parameter tested, including maximum observed plasma concentration, time to maximum observed concentration, minimum observed plasma concentration, area under the plasma concentration-time curve, and elimination rate constant.Conclusions: Atrasentan is well tolerated in both female and male cancer patients at doses of up to 60 mg/day with dose-limiting toxicity observed at 75 mg/day. The most frequently observed toxicities were headache, rhinitis, and edema. There was no statistically significant difference in atrasentan pharmacokinetics between sexes.

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“…61 The endothelin autocrine loop is upregulated in HRPC, possibly as a result of androgen ablation, and clinical studies show promising results with significant effects not only on the tumour cells, but also on bone metastases. 62 Atrasentan is well tolerated and no dose limiting toxicities were seen in phase I studies. However, in common with other targeted therapies, and unlike cytotoxic therapies such as docetaxel, phase II data for atrasentan are consistent with cytostasis, leading to delays in progression rather than a reduction in tumour burden.…”

Section: Future Directionsmentioning

confidence: 97%

The changing pattern of management for hormone-refractory, metastatic prostate cancer

James

Bloomfield

Luscombe

2006

Prostate Cancer Prostatic Dis

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Prostate cancer responds initially to hormonal manipulation by androgen withdrawal and peripheral androgen blockade. The inevitable progression to a hormone-refractory state is accompanied by an exacerbation of local symptoms and metastatic spread, principally to the bones, which has a considerable impact on quality of life and survival. Treatment of hormonerefractory prostate cancer is palliative, and surgery and radiotherapy are used for the relief of lower urinary tract symptoms and localized painful bony metastases. Systemic treatments are not widely accepted in this setting, but clinical trials have demonstrated the potential for bone targeting agents such as strontium-89 and the bisphosphonates to palliate painful bone metastases and to delay progression in certain settings. Chemotherapy with mitozantrone in combination with steroids has previously been shown to have palliative benefits and to delay progression. The additional costs incurred by the use of chemotherapy or bone-targeting therapies may be offset by gains in overall care with fewer in-patient admissions compared with steroid monotherapy . Recent clinical trials have demonstrated that docetaxel significantly improves patient quality of life, and importantly, increases survival. Future studies investigating the timing of chemotherapy, combinations with existing treatments or other novel therapies are underway.

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Suppression of Prostate Cancer Induced Bone Remodeling by The Endothelin Receptor a Antagonist Atrasentan

Abstract: Atrasentan suppressed markers of biochemical and clinical prostate cancer progression in bone and demonstrates clinical activity for hormone refractory prostate cancer.

Cited by 129 publications

References 16 publications

Hypercalcaemia of malignancy and basic research on mechanisms responsible for osteolytic and osteoblastic metastasis to bone

Hypercalcaemia of malignancy and basic research on mechanisms responsible for osteolytic and osteoblastic metastasis to bone

Dose-Ranging Study of the Safety and Pharmacokinetics of Atrasentan in Patients with Refractory Malignancies

The changing pattern of management for hormone-refractory, metastatic prostate cancer

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