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New Treatment May Help with Side Effects of Chemotherapy

By Eddy Ball
August 2009

Bruce Hammock, Ph.D.
Hammock, above, is shown with the insect that began his odyssey from basic to translational research - the hungry caterpillar. Hammock has enjoyed NIEHS support for his research since his first grant in 1979. (Photo courtesy of Bruce Hammock and the University of California, Davis)

Alan R. Parrish, Ph.D.
Parrish, above, led the TAMU team on the study and was first author. (Photo courtesy of Melany Borshack and TAMU Health Sciences Center)

A new study funded in part by NIEHS reports experimental findings that may help prevent a dangerous side effect of the widely used chemotherapeutic drug cisplatin. The findings, which were published in the June issue of Cell Biology and Toxicology, could one day offer hope for the estimated five to ten percent of cisplatin-treated patients who experience renal failure as a consequence of their treatment for lung, ovarian, testicular, bladder, and head and neck tumors.

The study (http://www.ncbi.nlm.nih.gov/pubmed/18386137?ordinalpos=5&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum) Exit NIEHS was conducted by NIEHS grantee Bruce Hammock, Ph.D. (http://cvec.ucdavis.edu/node/60) Exit NIEHS, of the University of California, Davis and a team of Texas A&M University (TAMU) researchers led by first author Alan R. Parrish, Ph.D. (http://medicine.tamhsc.edu/basic-sciences/sbtm/faculty/alan-parrish.html) Exit NIEHS The investigators demonstrated that increasing serum levels of the fatty acid 12-(3-adamantan-1-yl-ureiido)-dodecanoic acid (AUDA) effectively blocked an enzyme known as soluble epoxide hydrolase (sEH) that is implicated in the hypertensive and inflammatory effects of cisplatin in the kidneys of mice.

The treatment protocol involved injecting the n-butyl ester of the fatty acid (nbAUDA) in a vehicle solution into mice also treated with cisplatin. Because the treatment appears to be free of significant side effects, the protocol could give physicians an alternative to medications now in use that are not so benign. According to the study's authors, this novel approach may represent the first significant advance in clinical management of acute renal failure since the development of dialysis.

Mice in the experiments included a control group and groups that received one of three treatment protocols - cisplatin alone, nbAUDA alone, or both. The researchers also injected a separate group of mice with the vehicle solution to determine that the vehicle by itself had no effect on AUDA levels. Blood samples were analyzed at regular intervals during the course of treatment for levels of AUDA and a marker of renal damage - blood urea nitrogen (BUN).

The researchers found that treatment with nbAUDA resulted in elevation of AUDA in serum and produced a significant, if not complete, reduction in BUN levels for the mice administered both nbAUDA and cisplatin compared to those injected with cisplatin alone. After euthanizing the mice, the investigators examined the animals' kidneys by histology. While almost complete loss of tubular structure was evident in the kidneys of cisplatin-only mice, "tubules from nbAUDA/cisplatin mice look remarkably normal," the researchers reported - similar to mice in the control and nbAUDA-alone groups.

Experiments with humans should produce similar results, the authors explained, since sEH "represents a single known gene product with over 90 percent homology between rodent and human." They added that the viability of sEH-deleted mice suggests that side effects from inhibition of the enzyme should be minimal.

Along with funding from the TAMU vice president for research and the National Heart, Lung and Blood Institute, the study was supported by grants from NIEHS for research on hydrolytic enzymes (http://tools.niehs.nih.gov/portfolio/sc/detail.cfm?appl_id=7652200) and biomarkers of exposure to hazardous substances. (http://tools.niehs.nih.gov/portfolio/sc/detail.cfm?appl_id=7597037)

Citation: Parrish AR, Chen G, Burghardt RC, Watanabe T, Morisseau C, Hammock BD (http://www.ncbi.nlm.nih.gov/pubmed/18386137?ordinalpos=5&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum) Exit NIEHS. 2009. Attenuation of cisplatin nephrotoxicity by inhibition of soluble epoxide hydrolase. Cell Biol Toxicol 25(3):217-225.

From Caterpillars and Pesticides to Clinical Trials

This research on attenuating the side effects of cisplatin built on findings by Hammock and colleagues in several earlier studies of the effects of sEH inhibition on blood pressure, pain and inflammation (see November 2006 story "Distinguished Lecturer Outlines Hypertension Breakthrough").

In the early 1980s with funding from the NIEHS Superfund Research Program, Hammock began investigating the role of hydrolytic enzymes involved in the degradation of insect juvenile hormone, including esterases and epoxide hydrolases. His group then looked at the roles of similar enzymes in mammals, initially in search of ways to protect humans from the effects of pesticides. As his research progressed, however, Hammock discovered the potential benefits of inhibiting one of them - the soluble epoxide hydrolase - in the treatment of hypertension, pain and inflammation in mammals.

Blocking the enzyme has the effect of redirecting fatty acid metabolism away from the arachidonic acid pathway associated with inflammation and hypertension and has shown promise with several aspects of metabolic syndrome. A compound developed by Hammock to inhibit sEH, known as AR9281, was found to be safe and well tolerated in healthy volunteers and is currently undergoing Phase IIa clinical trial (http://www.aretetherapeutics.com/news/2009/060909.html) Exit NIEHS for treatment of diabetes.



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