[A new antitumor drug with immunomodulating activity, ubenimex (bestatin)]

Ubenimex (Bestatin) was discovered by Umezawa et al. in 1976 from the culture broth of Streptomyces olivoreticuli. Bestatin is a compound of low-molecular weight peptide and inhibits leucine aminopeptidase and aminopeptidase B which localized in cell membrane. Bestatin exhibited antitumor effect against murine syngeneic tumors including mouse colon 26 and C1498 leukemia, and also it was active against MNNG-induced rat tumor by oral administration. Combination treatment of mouse colon 26 with bestatin and mitomycin C, 5-FU or CDDP was effective for the life prolongation of the treated mice compared to mono-therapy alone. Bestatin was found to exhibit the antitumor effect through T lymphocyte stimulation, macrophage activation and bone marrow stem cell stimulation were also observed by bestatin treatment experimentally. Values of T cell subsets in cancer patients recovered to the normal levels by Bestatin treatment. Release of Interleukin-1 and -2 was enhanced by Bestatin treatment in vitro. In the phase I study, clinical optimal daily dose was estimated as 10-100 mg to give 2-3 times weekly or daily continuously. In the comparative clinical trials, Bestatin was found to be effective for the prolongation of survival time of the patients with acute non-lymphocytic leukemia after induction of complete remission in combination with maintenance chemotherapy. Minimal side effects were noted.