The neurotrophin-trk receptor axes are critical for the growth and progression of human prostatic carcinoma and pancreatic ductal adenocarcinoma xenografts in nude mice.
OBJECTIVE
Aberrant expression of trk receptor kinases and enhanced expression of various neurotrophins (NTs) have been implicated in the development and progression of human prostatic carcinoma and pancreatic ductal adenocarcinoma. We examined the antitumor efficacy of administration of NT neutralizing antibodies on the growth of established human prostatic carcinoma and pancreatic ductal adenocarcinoma xenografts in nude mice.


METHODS
In initial studies, tumor-bearing nude mice were treated with a mixture of NT antibodies [100 microg each of anti-nerve growth factor (NGF), anti-brain-derived neurotrophic factor, anti-NT-3, and anti-NT-4/5] or normal rabbit IgG (400 microg) intratumorally and peritumorally three times/week over a 15-day dosing period. In subsequent studies, tumor-bearing nude mice were treated with individual NT antibodies (100 microg), affinity-purified anti-NGF (0.1, 1.0, or 10.0 microg), or normal rabbit IgG (100 microg) using the same dosing schedule.


RESULTS
Treatment with the antibody mixture inhibited significantly the growth of TSU-Pr1 and AsPC-1 xenografts as compared with IgG-treated controls (maximal inhibition of 53 and 53%, respectively), whereas this treatment caused significant regression in PC-3 xenografts. Treatment of TSU-Pr1 xenografts with either anti-NGF or anti-NT-3 resulted in maximal tumor growth inhibition of 67 and 64%, respectively, whereas anti-brain-derived neurotrophic factor and anti-NT-4/5 did not inhibit tumor growth in this tumor model. Administration of various concentrations (0.1, 1.0, or 10.0 microg) of affinity-purified anti-NGF resulted in maximal TSU-Pr1 tumor growth inhibition of 49, 62, and 66%, respectively.


CONCLUSIONS
These data add further support for the therapeutic potential of disrupting trk-signaling events in select types of nonneuronal human cancers, specifically prostatic and pancreatic carcinomas.
Miknyoczki
Sheila J
SJ
Cephalon, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USA.
Wan
Weihua
W
Chang
Hong
H
Dobrzanski
Pawel
P
Ruggeri
Bruce A
BA
Dionne
Craig A
CA
Buchkovich
Karen
K
D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002455:Cell Division; D018450:Disease Progression; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009414:Nerve Growth Factors / Q000502:physiology*; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D011817:Rabbits; D020917:Receptor, trkA / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014183:Transplantation, Heterologous
D007074:Immunoglobulin G; D009414:Nerve Growth Factors; D020917:Receptor, trkA