The biochemical characterization of phase I and phase II components considered to be important in the metabolism of carcinogens and other xenobiotics was examined in two experimental models. This was done to elucidate the relationship between the process of carcinogenesis and the selection of a biochemical phenotype which could result in drug resistance, previously described in rat hepatocarcinogenesis models. / A model of mammary carcinogenesis in mice demonstrated no significant biochemical change relating to potential drug resistance among normal, preneoplastic and neoplastic mammary tissues. This is of particular interest since human breast cancer is usually quite drug sensitive at the start of the treatment. / Human colon cancer is probably induced by carcinogenic compounds present in the environmental dietary elements and also exhibits de novo resistance to most antineoplastic drugs. Most of the biochemical elements examined were found to be present in these colon tissues. Additionally, the detoxification pathways including glutathione and its related enzymes, were found to be significantly elevated in colon tumor versus normal adjacent mucosa. The molecular characterization of glutathione S-transferase (GST) isoenzymes using antibodies and cloned molecular probes to specific enzyme forms showed that the anionic form of GST (GST-$ pi)$ is greater in tumors than in the respective normal mucosa. The neutral form (GST-$ mu)$ is conversely decreased in tumor relative to normal. The cationic (GST-$ alpha)$ is present only in 30% of the samples examined, with no difference between tumor and adjacent normal mucosa. The expression of cytochrome P-450 isoenzymes was also examined in a similar fashion; a phenobarbital-inducible form was expressed in most colon tissues examined, and expression of the polycyclic aromatic hydrocarbons-inducible P$ sb3$-450 was present in some colon tissues while mRNA for P$ sb1$-450 was not detected in any. The biochemical alterations found in human colon could be the targets of therapeutic manoeuvers to enhance the efficacy of antineoplastic treatment of human colon cancer.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.74268 |
| Date | January 1989 |
| Creators | Mekhail-Ishak, Kamilia |
| 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 | Doctor of Philosophy (Division of Experimental Medicine.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 000933446, proquestno: AAINN63437, Theses scanned by UMI/ProQuest. |
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