Mitsuaki Maeda

Possible Chemopreventive Effects of Bovine Lactoferrin on Esophagus and Lung Carcinogenesis in the Rat

A milk component, bovine lactoferrin (bLF), previously shown by us to be a strong chemopreventive of colon carcinoma development, was examined for its influence on other organs using a rat multi‐organ carcinogenesis model. Male F344 rats, aged 6 weeks, were treated sequentially with diethylnitrosamine (DEN, i.p.), dihydroxy‐di‐N‐propylnitrosamine (DHPN, in drinking water) and N‐nitrosomethylbenzylamine (NMBA, s.c.) during the first 8 weeks (DDN treatment), and then bLF was administered in the basal diet, at a dose of 2, 0.2, 0.02 or 0.002%. Other groups were given DDN treatment or bLF alone as controls. All surviving animals were killed at week 41, and major organs were examined histopathologically for neoplastic lesions. In the esophagus, a tendency for reduction in development of papillomas was evident in the bLF‐treated animals, along with a significant suppression of relatively large‐sized papillomas (more than 50 mm3 volume) at the 0.2% dose (P<0.05, 11% of the control). The multiplicity of tumors (adenomas and carcinomas) in the lung was also decreased in animals fed 0.02% bLF (1.98±0.41 per cm2 lung tissue section, P<0.05) compared to the control group (3.48±0.33). No enhancing or inhibitory effects of bLF on tumor development in other organs were noted. The present results indicate that bLF exerts chemopreventive effects in the esophagus and lung in addition to the colon.

Antitumor activity of a new series of platinum complexes: trans(+/-)-1,2-cyclohexanediammineplatinum(II) conjugated to acid polysaccharides.

Complexes with trans (±)-1,2-cyclohexanediammineplatinum(II) conjugated to acid polysaccharides were synthesized and their antitumor activities were tested in female CDF1 mice with intraperitoneal leukemia L1210 cells. Platinum was released from the polymers under physiological conditions, with half-lives from 3.3 to 19.3 h. A hyaluronic acid-supported complex was the most effective against the tumors (all six mice survived for 60 days). The group given a chondroitin polysulfate-supported complex had five survivors, the chondroitin sulfate A group also had five, the chondroitin sulfate C group had three and the heparan sulfate group had two. Part of the antitumor activity was due to increased efficacy of the polymers. The bioavailability of these complexes is high. Therefore, acid polysaccharides should be a good system for delivering antitumor platinum complexes.

Effect of bis(bilato)-1,2-cyclohexanediammineplatinum(II) complexes on lung metastasis of B16-F10 melanoma cells in mice.

New platinum(II) complexes, bis(bilato)-1,2-cyclohexanediammineplatinum(II) which were lipophilic and water-miscible, were tested for antitumor activity against lung nodules from intravenously injected B16-F10 melanoma cells in C57BL/6 mice by intravenous administration of the complexes in water suspension form. Among them, DACHP(litho)2 and DACHP(urso)2 had high antitumor activity but others had no activity. The antitumor activity of DACHP(urso)2 was increased significantly by injecting it three times; T/C was over 280% with 100-day survivors of 3 of 6 mice tested. Large amounts of total platinum were found in lung and liver tissues by atomic absorption spectroscopy after single intravenous injection of DACHP(urso)2 suspension in ICR mice.

Antitumor activity and tissue distribution of bis(bilato)-1,2-cyclohexanediammineplatinum(II) complexes in BDF1 mice with murine reticulum cell sarcoma (M5076)

Murine reticulum cell sarcoma (M5076) was subcutaneously implanted into BDF1 mice and then the antitumor activity of seven micelle-forming type platinum complexes was tested. The antitumor activity of bis(hyodeoxycholato)-trans-(+/-)-1,2-cyclohexanediammineplatinu m(II)(t-DACHP (hyo)2) was highest (95% inhibition of growth), and it was dose dependent with a large therapeutic index. This was followed by bis-(chenodeoxycholato)-trans(+/-)(cis)-1, 2-cyclohexanediammineplatinum(II)(t(c)-DACHP-(cheno)2) (49% inhibition) and bis(ursodeoxy-cholato)-trans(+/-)-1,2-cyclohexanediammine platinum (II) (t-DACHP(urso)2) (48% inhibition). t-DACHP(hyo)2 and t-DACHP(urso)2 inhibited sarcoma 180 growth (63% and 33%, respectively). The organ distribution of the complex with the highest antitumor activity was compared with that of a complex with negligible antitumor activity. The total Pt levels were significantly higher in tumor tissue from mice given the more active complex than in tumor tissue from mice given the less active complex. Pt levels in the kidney and the spleen showed a similar pattern, but the lung tissue Pt levels were significantly higher in mice given the less active complex.

Triazine Derivatives Inhibit Rat Hepatocarcinogenesis but Do Not Enhance Gap Junctional Intercellular Communication

We report here novel candidate chemopreventive agents active against experimental hepatocarcino‐genesis. The triazine derivatives 6‐(2‐chlorophenyl)‐2,4‐diamino‐l,3,5‐triazine (2CPDAT), 6‐(3‐chlorophenyl)‐2,4‐diamino‐l,3,5‐triazine (3CPDAT), 6‐(4‐chlorophenyl)‐2,4‐diamino‐l,3,5‐triazine (4CPDAT), 6‐(4‐pyridyl)‐2,4‐diamino‐l,3,5‐triazine (PyDAT), and 6‐(pyridine JV‐oxid‐4‐yl)‐2,4‐diamino‐l,3,5‐triazine (PyNODAT), synthesized in our laboratory, in addition to 6‐(2,5‐dichloro‐phenyl)‐2,4‐diamino‐l,3,5‐triazme (DCPDAT), or irsogladine, which is a widely used anti‐ulcer drug, were investigated for potential chemopreventive effects in a rat liver medium‐term bioassay system. A significant inhibitory influence on enzyme‐altered liver foci was found for 2CPDAT, 3CPDAT, 4CPDAT, and PyNODAT, but not for DCPDAT or PyDAT, The involvement of gap jnnctional intercellular communication in the inhibition was studied, but no change in gap Junctional intercellular communication capacity in rat liver cells in vitro or in gap junction protein (connexin 32) expression in rat liver in vivo was noted. These results indicate that, although these irsogladine analogues exert inhibitory effects on rat liver carcinogenesis, their action is independent of modification of gap Junctional intercellular communication.