Haruki Ogawa

Activation of macrophage function by intraperitoneal administration of the streptococcal antitumor agent OK-432

Motility, adhesiveness, IL1 production, and inhibition of tumor cell growth in vitro were examined in murine peritoneal macrophages obtained after intraperitoneal injection of a streptococcal preparation OK-432, heat-inactivated OK-432 (HI-OK-432), and thioglycollate medium (TG). By varying the interval between intraperitoneal injection of OK-432 and the harvest of peritoneal macrophages, it was found that OK-432 induced a time-dependent multi-step alteration of these properties: step I increased motility on day 1: step II increased adhesiveness on day 2; and step II increased inhibition of tumor cell growth and IL1 production. During step III, the peritoneal macrophage population, including Ia-bearing cells, increased dramatically in the peritoneal cavities of OK-432-treated mice. In contrast, injection of either HI-OK-432 or TG, which lack antitumor activity in vivo, initiated steps I and II, but not step III. The Ia-bearing macrophages induced by OK-432 showed high ability of IL1 production, but low growth inhibitory activity against tumor cells. Based on these results, OK-432 seems to be performing a dual function: eliciting a new population of macrophages to the site of injection (heat stable function), and inducing two different populations of antitumor macrophages and Ia-bearing macrophages (heat unstable function).

A biochemical study of the phagocytic activities of tuftsin and its analogues.

The effects of tuftsin and one of its analogues (4 [lys]-tuftsin) on phagocytosis of Staphylococcus aureus and Candida albicans were investigated in mice and rabbits. Mice were intravenously or orally administered 1-25 mg of 4 [lys]-tuftsin per kg daily for 4 to 7 days. After the mice were further treated with cyclophosphamide, they were intravenously challenged with C. albicans. More than 50% of the mice infected with C. albicans were killed within 7 days, although only 20% to 40% of those infected with the same microbes after 4 [lys]-tuftsin treatment died. A combination of 4 [lys]-tuftsin and an antibiotic was found to be somewhat more effective than either one alone. Further, pretreatment with 4 [lys]-tuftsin depressed microbial growth in the kidneys of mice bearing S-180 tumors. Rabbit peritoneal macrophages and polymorphonuclear leukocytes were harvested by intraperitoneal injection of liquid paraffin and of glycogen solution, respectively. For in vitro study of phagocytosis, rabbit macrophages of polymorphonuclear leukocytes were incubated in Hanks solution together with S. aureus and the number of survivors was determined. Enhanced engulfing activity of macrophages and increased bactericidal activity of polymorphonuclear leukocytes were shown by the in vitro phagocytosis experiments. It is expected that 4 [lys]-tuftsin will be effective against infectious disease, especially in immunocompromised hosts such as patients with malignant tumors.