Modern cancer therapy has explored the use of enzymatically acting toxins coupled to specific binding proteins in an attempt to destroy specific cell populations. In light of these new therapies we have synthesized two hormonotoxins (HTs): (i) composed of the ribosome inactivating plant protein gelonin conjugated to luteinizing hormone (LH), (ii) gelonin conjugated to human chlorionic gonadotropin (hCG), both through a disulfide bond. / Characterization of both conjugates was carried out by SDS-PAGE analysis, radioimmunoassay and Western blotting (using polyclonal antibodies against both the hormone and the toxin). In addition, bioactivity of the hormonotoxins was determined by their ability to bind LH receptors in testicular membrane preparations. MA-10 cells showed a significant reduction in protein synthesis following a 24 hour exposure to the cytotoxic conjugates. / In vivo studies were carried out using the LH-gelonin hormonotoxin. Intravenous injections of $ sp{125}$I-HT into 28-30 day-old pseudopregnant mice and determination of radioactivity in the ovaries, kidneys, liver, thyroid, brain, and blood helped to establish preliminary results on the uptake of hormonotoxin by these tissues. Study of the cytotoxic effects of the conjugate in vivo in normal male mice (following a three week period of injection), revealed a significant reduction in testosterone production in animals which received the highest concentrations of hormonotoxin. In addition, treatment of animals with the separate components of the conjugate (same pattern and duration of treatment), established specificity of the effect exerted by the hormonotoxin. Treatment with the LH-gelonin hormonotoxin caused production of antibodies to both components of the conjugate. Results obtained from these studies have helped to establish the groundwork for the effects of HT in vivo in normal mice. Overall, the research on these HTs had provided encouraging information for their potential use as therapeutic agents. (Abstract shortened by UMI.)
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.22845 |
| Date | January 1995 |
| Creators | Apostolakos, Persefoni |
| Contributors | Sairam, M. R. (advisor) |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Master of Science (Department of Physiology.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 001467512, proquestno: MM07994, Theses scanned by UMI/ProQuest. |
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