Abstract: 430

A GONADOTROPIN-RELEASING HORMONE AGONIST (GnRH-A) LINKED TO POKEWEED ANTIVIRAL PROTEIN (PAP) DECREASES THE ABILITY OF THE PITUITARY GLAND TO SECRETE LH.

Terry M. Nett^{1 *}, Matthew C. Allen¹ , Majiec Wieczorek² , L. Michael Glode³
Animal Reproduction and Biotechnology Laboratory, Colorado State University, Fort Collins, CO 80523 ¹
Gonex, Inc., 7034 Indian Peaks Trail, Boulder, CO 80301 ²
Division of Oncology, University of Colorado Health Sciences Center, Denver, CO 80262 ³

We are attempting to develop a permanent, non-surgical means of sterilizing animals (based on linking a cytotoxic agent to a GnRH-A) that would be effective in either sex of a wide variety of species. The GnRH-A should deliver the cytotoxin specifically to cells with GnRH receptors and it should destroy those cells. Our objective was to test the ability of a GnRH-A conjugated to PAP (GnRH-PAP) to inhibit LH secretion in ovariectomized ewes. After conjugaton, GnRH-PAP retained full cytotoxic activity whereas the ability to bind to receptor was reduced by 5-fold. Groups of five ewes were administered 0.58 mg (LOW) or 2.9 mg (HIGH) GnRH-PAP i.v.; representing 2 or 10 µg GnRH-A receptor binding activity, respectively. Each ewe was challenged with 20 µg GnRH i.v. at -2, 1, 2, 3, and 4 weeks relative to treatment with GnRH-PAP and at ~7 week intervals thereafter. Blood samples for analysis of LH were collected at 30-min intervals for 4 h after each challenge. Total LH released was assessed by measuring area under the GnRH response curve (AUC). Treatment with the LOW dose resulted in a gradual reduction in AUC to about 40% of the pretreatment level (P<0.05) within 4 weeks where it remained for the succeeding 6 months. Treatment with the HIGH dose of GnRH-PAP resulted in a more rapid decrease in AUC such that it reached ~40% of pretreatment within 1 week (P<0.05) with no further decrease. As in the low group, AUC for the HIGH group remained at ~40% of the pretreatment for more than 6 months. These data indicate that administration of GnRH linked to a cytotoxic agent can decrease the ability of the pituitary gland to secrete LH. The fact that there was no increase in AUC for at least 6 months after treatment suggests that the cytotoxic effect may be permanent

    This abstract is being presented on Tuesday, August 3 at 8:00 AM to 10:15 AM at CUB 2nd Floor Ballroom.