Acute pancreatitis associated with administration of a nitric oxide synthase inhibitor in tumor-bearing dogs.
BACKGROUND
Nitric oxide synthase (NOS) inhibitors have been investigated as potential cytotoxic agents to treat tumors lacking p53 function. Furthermore, their ability to reduce tumor blood flow can be combined with drugs that are specifically designed to kill cells that are hypoxic or to improve temperatures during local heat (hyperthermia) treatment of tumors. This paper reports the unexpected development of acute pancreatitis in two tumor-bearing pet dogs that were treated with the NOS inhibitor, NG-nitro-L-arginine methyl ester (L-NAME) during administration of local hyperthermia.


METHODS
Prior to the use of L-NAME in tumor-bearing dogs, purpose-bred beagles were studied. Following induction of inhalation anesthesia, local hyperthermia was applied to either normal thigh muscle (beagles) or tumors (tumor-bearing dogs). Once a thermal steady state was achieved, L-NAME was administered and temperature monitoring continued. Animals were observed after treatment for evidence of toxicity.


RESULTS
The beagles tolerated the treatment well, with no side effects noted either clinically or by routine CBC or blood chemistry analyses. In contrast, the first two tumor-bearing dogs accrued onto the phase I study developed acute pancreatitis in the immediate post-treatment period which necessitated hospitalization and intensive care. The trial was stopped. Both dogs had intercurrent risk factors which predisposed them to development of pancreatitis, although neither had a history of symptoms of pancreatitis at the time the hyperthermia + L-NAME treatment was given.


CONCLUSIONS
We conclude that caution should be exercised when considering NOS inhibition for cancer treatment. Careful evaluation of history and health status as well as recognition of potential risk factors may be key in avoiding potentially fatal complications. This study demonstrates the value of performing potentially harmful treatments in tumor-bearing dogs prior to introduction into the human clinic.
Poulson
J M
JM
Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA.
Dewhirst
M W
MW
Gaskin
A A
AA
Vujaskovic
Z
Z
Samulski
T V
TV
Prescott
D M
DM
Meyer
R E
RE
Page
R L
RL
Thrall
D E
DE
D000208:Acute Disease; D000818:Animals; D001859:Bone Neoplasms / Q000188:drug therapy / Q000662:veterinary; D003131:Combined Modality Therapy; D004285:Dogs; D004791:Enzyme Inhibitors / Q000009:adverse effects*; D017809:Fatal Outcome; D005260:Female; D005354:Fibrosarcoma / Q000188:drug therapy* / Q000662:veterinary; D006979:Hyperthermia, Induced; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000009:adverse effects*; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000662:veterinary; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D009918:Orbital Neoplasms / Q000188:drug therapy* / Q000662:veterinary; D010195:Pancreatitis / Q000139:chemically induced* / Q000662:veterinary; D012509:Sarcoma / Q000188:drug therapy / Q000662:veterinary
D004791:Enzyme Inhibitors; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester