Cancer Control Research
7R03CA072393-02
Holcombe, Randall F.
IMMUNOMODULATION BY LEVAMISOLE FOR CANCER DETECTION
AbstractDESCRIPTION (Applicant's Description) Cancer prevention is an evolving field
in clinical oncology. In addition to lifestyle changes (diet, smoking),
there is evidence that pharmacologic intervention with cancer
"chemopreventive" agents such as calcium, non-steroidal anti-inflammatory
drugs and beta-carotene may be beneficial for many patients. Because of the
difficulties in measuring and quantitating changes in the activity of the
immune system, few immunomodulatory agents have been tested as possible
candidates for cancer chemoprevention. Levamisole (LMS) is an
immunostimulant which is utilized along with 5-fluorouracil (5FU) in the
adjuvant therapy of patients with surgically resected stage III colon
cancer. This agent is ineffective in the treatment of clinically apparent
cancer but appears effective against microscopic disease, likely through
stimulation of anti-tumor aspects of the immune system. Therefore, it is
possible that LMS may be useful as a cancer prevention agent. Initially in
this proposal, several activities of LMS which have been defined previously
in patients with colon cancer will be evaluated in normal volunteers to
ascertain the potential utility of LMS as a cancer chemoprevention agent.
Specifically, the proportion and activity of natural killer (NK) cells will
be evaluated. Increases in NK cells in colon cancer patients receiving LMS
correlates with longer disease-free survival. The ability of LMS to induce
a Th1-type immune response in vivo and it's activity in priming CD4-positive
T-cells to be induced toward a Th1 differentiation pathway in vitro will be
studied. Previous studies have suggested that LMS is synergistic with IL12
in the promotion of a Th1 response. A Th1 immune response is critical for
immunity against viral and parasitic infections and against tumors.
Finally, because LMS induces changes in MHC class 1 expression on colon
cancer cell lines in vitro, theoretically making them more susceptible to
lysis by NK cells, the effect of LMS on MHC class 1 expression on buccal
mucosal cells in vivo will be determined. Information obtained in these
pilot studies will then be utilized to develop a limited double-blinded
placebo-controlled trial with crossover design in patients with colonic
polyps. This aspect of the proposal will be of longer duration and will
attempt to validate immunologic intermediate endpoints defined in the
initial pilot phase. Overall, these studies will involve a clinical
protocol with a dose-response design to evaluate the immunologic effects of
LMS and will provide the foundation for future investigations of LMS as a
cancer chemoprevention agent.
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