Edotelina Y Carcinomas

uropepAtrasentan, an Endothelin-Receptor Antagonist for
Refractory Adenocarcinomas: Safety and Pharmacokinetics
By Michael A. Carducci, Joel B. Nelson, M. Kathy Bowling, Theresa Rogers, Mario A. Eisenberger, Victoria Sinibaldi,
Ross Donehower, Terri L. Leahy, Robert A. Carr, Jeffrey D. Isaacson, Todd J. Janus, Amy Andre, Balakrishna S. Hosmane,
and Robert J. Padley
Purpose: Endothelinreceptors, particularly the ETA
receptor, have been shown to participate in the pathophysiology of prostate and other cancers. Atrasentan,
an endothelin antagonist, binds selectively to the ETA
receptor. This study evaluated the safety, pharmacokinetics, and maximum-tolerated dose of atrasentan in
cancer patients.
Patients and Methods: Patients who were 18 years
or older and had histologicallyconfirmed adenocarcinoma refractory to therapy enrolled in this 28-day,
open-label, phase I study. Enrollment was planned for
cohorts of three patients at doses escalating from 10 to
140 mg/d. When any patient had dose-limiting toxicity,
that cohort was expanded. The primary outcome variable was safety; secondary outcome variables were
pharmacokinetics, tumor response, and pain relief.
Results:Thirty-one cancer patients (14 prostate)
were treated at daily atrasentan doses of 10, 20, 30,
45, 60, and 75 mg (n
3 to 8 per cohort). The most
common adverse events, such as rhinitis, headache,

asthenia, and peripheral edema, were reversible on
drug discontinuation and responded to symptom-specific treatment. Reversible hemodilution was apparent
in laboratory findings and weight gain.Clinically significant headache was the dose-limiting adverse event;
the maximum-tolerated dose was 60 mg/d. Pharmacokinetics were dose-proportional across the 10- to
75-mg dose range. Atrasentan was rapidly absorbed;
the time to maximum observed concentration was approximately 1.5 hours. The terminal elimination halflife was approximately 24 hours, and steady-state
plasma concentrations wereachieved within 7 days.
Decreases in prostate-specific antigen and pain relief
were noted in a patient subset.
Conclusion:
Adverse events were consistent with
atrasentan’s pharmacologic vasodilatory effect. Linear,
dose-proportional pharmacokinetics suggest that atrasentan can be easily and consistently dosed.
J Clin Oncol 20:2171-2180. © 2002 by American
Society of Clinical Oncology.

HEENDOTHELIN FAMILY is composed of three
isopeptides, ET-1, -2, -3, which mediate pleiotropic
activities in a wide array of tissues.1,2 Initially identified as
a product of endothelial cells with potent vasoconstrictive
and mitogenic properties, ET-1 is the most common circulating form of endothelin and is also found in many
epithelial-derived tumors.3-5
ET-1 actions are mediated via two G-protein–coupled
receptors, ETA and ETB, which are distinguished by different binding affinities for the endothelins. The ETB receptor
binds the three isotypes with equal affinity, functioning as a
clearance receptor and modulator of ET-1 secretion.6 In
contrast, the caveolae-based ETA receptor binds ET-1 with
a higher affinity than the other isoforms, directly stimulates
proliferative responses inneoplastic and normal cells, and
potentiates other growth factors commonly implicated in
malignant growth.5-8 ET-1 activation of the ETA receptor
also prevents apoptosis.9 There are multiple pathways
whereby the ET-1/ETA axis may contribute to the manifestations of cancer, including the modulation of angiogenesis,
blood flow, nociception, and bone deposition.10-15
A dysregulation of theendothelin axis leading to
increased ET-1 production favors tumor growth. This
finding was initially described in prostate cancer patients
in whom increased plasma ET-1 concentrations were

greatest with metastatic, hormone-refractory disease.16
Furthermore, prostate cancer cell lines, primary tumors,
and metastatic prostate cancer lesions express increased
amounts of ET-1.8,16 Concomitant with...