Defense Date


Document Type


Degree Name

Doctor of Philosophy


Pharmacology & Toxicology

First Advisor

Albert E. Munson


Studies were undertaken to characterize the immune status of mice bearing the Lewis lung carcinoma (LLC) and to maximize the cure rate of LLC and Madison l09 carcinoma (Ml09) bearing mice by employing the immunomodulator maleic vinyl ether (MVE) in combination with surgery or radiotherapy.

The pattern of immunodeficiency in mice bearing the LLC appeared to be in contrast to most studies. LLC mice with a minimal tumor burden were found to have a diminished ability to phagocytize sheep erythorcytes (SRBC) or elicit an antibody response to the same antigen. Vascular clearance and phagocytic uptake of 51Cr-labeled SRBC into reticuloendothelial (RE) organs exhibited a triphasic response. Liver phagocytosis and vascular clearance were markedly suppressed 24 and 48 hours after tumor inoculation. The initial decrease in RE function was followed by a phase of increased activity which progressively decreased to control levels with increasing tumor burden. IgM antibody forming cells to SRBC were reduced to 18% of control values 7 days after inoculation and by day 27 no antibody forming cells could be detected in the LLC bearing mice. In contrast, delayed type hypersensitivity to SRBC remained intact until day 17 and no significant changes in inflammatory activity were noted. Surgical excision of the primary tumor burden on day l4 had no effect on survival time but partially restored the suppressed immune functions.

Accordingly, immunotherapeutic regimens were designed to treat early in the disease state or after cytoreductive therapy in an effort to have immunocompetent animals with a minimal tumor burden. Yet, systemic MVE treatment by itself, or in combination with surgical excision or local radiotherapy of the primary tumor was ineffective in prolonging life span. Intravenous MVE treatment also failed to exhibit antitumor activity against the LLC when the metastatic tumor burden was markedly reduced by multiple cyclophosphamide injections. In contrast to systemic MVE treatment, an acute intralesional injection of MVE proved to be efficacious by increasing life span by 36%. Moreover, the combination of intralesional MVE with local radiation of the primary LLC tumor significantly prolonged survival time over the radiation controls.

The M109 was shown to be relatively responsive to MVE treatment. Multiple injections of MVE in doses ranging from l0 to 50 mg/kg significantly prolonged the life span of the host and inhibited the growth of the primary tumor. The efficacy of MVE therapy appeared to be dependent on the distribution of the polymer. Weekly intralesional injections of MVE were most effective in prolonging life span early in the disease state, presumably by inhibiting the metastatic process. As the tumor metastasized to the lung only MVE introduced directly into the metastatic tumor bed by intrapleural or inhalation administration proved to be efficacious in prolonging life span. These data emphasize the importance of drug distribution in the treatment of neoplasia with nonspecific immunotherapy.


Scanned, with permission from the author, from the original print version, which resides in University Archives.


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