Biological Response-Modifying Properties of the Alkaloid Derivative Ukrain (NSC631570)
A. LIEPINS,* E. M. SOTOMAYOR, D. M. LOPEZ, and J. W. NOWICKY
Memorial University, Faculty of Medicine. St. John's. Newfoundland,
Canada AI B 3V6*;
University of Miami School of Medicine. Miami. Florida 33124; and
Ukranian Anticancer Institute, Laimgrubengasse 19/7. A-1060 Vienna. Austria
The discovery and development of immune response-modifying agents, which could be effective in a clinical setting for the treatment of cancer, has become a promising and important goal in immunotherapy. The full therapeutic potential of the existing biological response modifiers (BRMs) has not been fully realized because of their undesirable side effects when used at the concentrations required for maximum biological activity (4). Thus. the notification and characterization of new compounds without deleterious side effects would enhance the prospects of immunotherapy as a practical and effective cancer treatment modality.
A new and promising area of research has evolved from biochemical phytotherapy, in which plant alkaloids as well as their semisynthetic derivatives have been found to be effective immunomodulators in animal models and in cancer patients (5, 6). For example, the indolizidine alkaloid swainsonine has been reported to inhibit experimental lung metastasis of melanoma cells when administered systemically to mice in a prophylactic setting. The inhibition of pulmonary metastasis was found to be mediated by the host natural killer (NK) cells. Moreover, swainsonine induced an increase in the number of murine splenocytes and in macrophage cytotoxicity (5).
Similarly, alkaloids from the plant Chelidonium majus L. conjugated to thiophosphoric acid yield a triaziridide compound denoted as Ukrain, which, in preliminary clinical studies, has been found to have iimmunomodulatory activity (6). The major immune effects of this alkaloid derivative are an increase in the total T-lymphocyte number and a normalization of the T-helper/T-suppressor cell ratios, without affecting immunoglobulin levels, complement components, and acute-phase proteins in scrum (7). The present studies were undertaken to investigate me possible mechanism by which Ukrain may mediate its therapeutic effects in cancer patients.