Peritoneal carcinomatosis is a complex clinical-pathological condition and most patients with this disease would die within 6 months. The disadvantage of systemic cancer therapy is that only a small portion of the administered drug can reach the tumor cells, and side effects could occur due to its wide distribution in the body. In recent years, cytoreductive surgery combined with intraperitoneal chemotherapy has been the effective way for the treatment of peritoneal carcinomatosis. But the anticancer agents in aqueous form can be easily absorbed through capillaries below the large serosal surface into the systemic circulation, and it is difficult to retain the drug at a high concentration for a long time in the peritoneal cavity. The ideal drug for intraperitoneal chemotherapy should have a high molecular weight, a prolonged retention in the peritoneal surface, and increase drug exposure to tumor cells, decrease drug absorption and hence reduce systemic toxicity. ABZ (albendazole) with its properties of poor water solubility and strong anticancer effects could be a potential effective agent for the treatment of peritoneal carcinomatosis. The aims of this study are: to compare oral versus i.p administration of ABZ, study pharmacokinetic characteristics of ABZ in i.p administration; to study the efficacy ofABZ on early, middle and later stages of cancer development, to find out the possible antitumor effect of ABZ in suppressing cancer cell proliferation, ascites control and longer survival of mice with peritoneal carcinomatosis; to solve the occurring problems during ABZ i.p administration, reduce side effects and increase the drug efficacy; to investigate possible mechanisms ofABZ suppressing tumor proliferation and ascites formation. A series of experiments were designed in order to achieve the study objectives. The pharmacokinetic study of ABZ gives some dynamic characteristics by oral versus i.p administration in rabbits. Three sets of experiments of ABZ treatment were performed on different stages peritoneal carcinomatosis arising from the OVCAR-3 cancer cells in nude mice, from which the efficacy of ABZ in suppressing tumor growth and ascites formation by i.p administration is clearly demonstrated. The increased solubility of ABZ with three surfactants and in human ascites was carried out in different tests, and the combination of ABZ with Tween 80 has achieved better control of peritoneal carcinomatosis when given by i.p administration. The results from this study have revealed for the first time the capacity of ABZ suppressing VEGF (vascular endothelial growth factor) and ascites formation profoundly, confirmed that ABZ has potent anti-proliferation effects on ovarian cancer cells (OVCAR3); it suppressed tumor growth in early stage of cancer development; and prolonged survival of all ABZ treated mice by i.p administration. The major contributions from this study are: ABZ i.p treatment increases survival, inhibits ascites production, reduces tumor burden at relatively early stage of cancer, changes tumor morphology and reduces vascular density, reduces CA-125 (cancer antigen 125) and VEGF level, decreases in vitro VEGF secretion, and down regulates VEGF mRNA expression. The study results concluded that ABZ could be a potential anticancer agent for the treatment of peritoneal carcinomatosis by i.p administration. The significance of this study is that the fundamental results obtained from all experiments, including the major contributions and other associated works, have provided the scientific foundation for a clinical trial. Currently the maximum tolerated dose of ABZ i.p treatment in mice is on going before clinical trial and studies in related area of ABZ anticancer pathways are continuing in our laboratory.
| Identifer | oai:union.ndltd.org:ADTP/258362 |
| Date | January 2007 |
| Creators | Cai, Zhao Yan, Clinical School - St George Hospital, Faculty of Medicine, UNSW |
| Publisher | Awarded by:University of New South Wales. Clinical School - St George Hospital |
| Source Sets | Australiasian Digital Theses Program |
| Language | English |
| Detected Language | English |
| Rights | Copyright Cai Zhao Yan., http://unsworks.unsw.edu.au/copyright |
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