Hiroki Mitsui

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).

Effect of recombinant human erythropoietin on anticancer drug-induced anaemia.

Summary. Anaemia was induced in rats with fluorouracil (5‐FU) or cisplatin (CDDP) and the mechanisms of anaemia induction were analysed. Furthermore, the therapeutic effects of recombinant human erythropoietin (rHu Epo) on these anticancer drug‐induced anaemias were investigated.

Toxicological and Tumoricidal Evaluations of a New Platinum Complex, (–)‐(R)‐2‐Aminomethy lpyrrolidine (1,1‐cyclobutanedicarboxylato) platinum (II) Monohydrate, in Rats

The toxicities and antitumor activity of a new anticancer platinum compound, (‐)‐(R)‐2‐amino‐methylpyrrolidine(l,l‐cyclobutanedicarboxylato)platinum(II) monohydrate (DWA2114R), were examined in rats by single intravenous injection in comparison with those of cis‐diammine(1,1‐cyclobutanedicarboxylato)platinum(II) (CBDCA) and cis diamminedichloroplatinum(II) (CDDP). The lethal dose (LD) of DWA2114R (100 mg/kg) or CBDCA (80 mg/kg) caused a slight decrease in body weight <10%) and no significant change in the levels of blood urea nitrogen and urinary sugar and protein. In contrast, a sub‐LD level of CDDP (8 mg/kg) seriously decreased body weight (20%) and markedly elevated the levels of these nephrotoxicity parameters. Monitoring the numbers of peripheral blood cells for 3 weeks after the drug injection revealed that all three drugs showed severe thrombocytopenia, moderate leukopenia and slight anemia. However, CBDCA induced the most severe thrombocytopenia among these drugs. The number of platelets was reduced by 60% in rats injected with a half LD of CBDCA. A moderate reduction in platelet count (35–43%) was caused by an equitoxic dose of DWA2114R or CDDP, but abated about 3 days faster than that caused by CBDCA. Interestingly, only CDDP caused an irreversible anemia. Each drug showed a potent antitumor activity at weakly toxic doses against Walker 256 carcinosarcoma transplanted intramuscularly into rats. These results indicate that DWA2114R could be a promising new platinum anticancer agent with an improved toxicity profile.