Biomedical subjects

K Akamatsu

Publications and source records attributed to K Akamatsu.

96 records · Page 6Linked to original sources

PubMedDate not supplied

Antitumor effects of three platinum complexes, (-)-(R)-2-aminomethylpyrrolidine(1,1-cyclobutanedicarboxylato)-platinum (II) monohydrate (DWA2114R), cis-diammine-(1,1-cyclobutanedicarboxylato)platinum(II) (CBDCA) and cis-diamminedichloroplatinum(II) (CDDP), in mice.

(-)-(R)-2-Aminomethylpyrrolidine(1,1-cyclobutanedicarboxylato++ +)platinum(II) monohydrate (DWA2114R), cis-diammine(1,1-cyclobutanedicarboxylato)platinum(II) (CBDCA) and cis-diamminedichloroplatinum(II) (CDDP) were compared for their antitumor effects and nephrotoxicity-inducing activities at the same dosage (1/8, 1/4, 1/3, 1/2, 2/3 or 3/4 of the LD10 or LD10) on the basis of their intravenous lethal doses in mice. DWA2114R was effective against murine tumor lines, Colon 26 and Colon 38 carcinomas, M5076 ovarian sarcoma and P388 L1210 leukemias, implanted subcutaneously (s.c.). Triple injection every other day of DWA2114R was more effective than a single injection at each sublethal dose. The antitumor effects of DWA2114R against these tumors were more effective than or were similar to those of CBDCA and CDDP. The antitumor effect against CDDP-resistant L1210 leukemia implanted s.c. was only observed in the treatment of DWA2114R, but not in CBDCA and CDDP. No excellent antitumor effects of three platinum complexes were observed against Lewis lung carcinoma and B16 melanoma implanted s.c. even at triple injection every other day, and no effect was obtained against Meth-A fibrosarcoma under similar conditions. While the treatment of CDDP showed marked increases in levels of blood urea nitrogen and of urinary protein and sugar at effective doses in the antitumor evaluations, the treatment of DWA2114R as well as CBDCA showed no increase in these parameters. These results indicate that DWA2114R represents a desirable second generation antitumor platinum complex.

Animals↗

PubMedDate not supplied

In vitro antitumor mechanism of a new platinum complex, (-)-(R)-2-aminomethylpyrrolidine(1,1-cyclobutanedicarboxylato+ ++) platinum(II).

The antitumor mechanism of (-)-(R)-2- aminomethylpyrrolidine (1.1-cyclobutanedicarboxylato)platinum(II) (DWA2114R) was examined using cultured murine L1210 leukemia cells by estimating its effects on parameters such as proliferation, macromolecular synthesis, morphology and cell cycle progression. Each parameter was estimated in cells concomitantly exposed to the drug for 24-48 hr. More than 0.1 microM of DWA2114R markedly inhibited cell proliferation as well as DNA synthesis, and it decreased in mitotic index in a concentration-dependent manner. One microM of DWA2114R decreased DNA synthesis by 80% in the cells treated for 24 hr, while the inhibition of RNA synthesis was less than 40%. A significant inhibition of protein synthesis was caused only by treatment with a high concentration (100 microM) of the drug. Under complete cytostatic conditions (10 microM of DWA2114R), cell volume markedly increased and about 40% of the total cells were polynucleate. In addition, flow cytometrical analysis revealed that most of these cells were accumulated in the G2/M phase of the cell cycle, and a new peak located in the G2/M phase of tetraploid cells emerged. On the other hand, the cells treated with 100 microM of the drug did not increase in volume and their progress in the cell cycle was almost completely blocked.

Animals↗

PubMedDate not supplied

Antitumor activity of a new platinum complex, 2-aminomethyl-pyrrolidine (1, 1-cyclobutanedicarboxylato) platinum (II).

One hundred cis-diamminedichloroplatinum (II) (CDDP) analogs have been evaluated for antitumor activity in male CDF1 mice subcutaneously (s.c.) implanted with tumor fragments of Colon 26 carcinoma. Among the complexes tested, 2-aminomethyl-pyrrolidine (1, 1-cyclobutanedicarboxylato) platinum (II) (DWA 2114) had the best antitumor effect. The mice intraperitoneally (i.p.) injected with DWA 2114 at a dose of 40 mg/kg/day on days 4, 6 and 8 after inoculation showed a 97% growth inhibitory ratio (GIR) on day 14 compared to the non-treated control mice. We evaluated the inhibitory effects of DWA 2114 on other tumors, such as Colon 38 carcinoma, Ca 755 mammary adenocarcinoma and L1210 leukemia, and found that it also had antitumor effects on various kinds of tumors. The nephrotoxicity-inducing activity of DWA 2114 and CDDP was evaluated in normal BDF1 mice, as indicated by changes in blood urea nitrogen (BUN) at almost the maximum tolerated dose (MTD) (DWA 2114: 100 mg/kg, CDDP: 12 mg/kg). DWA 2114 had no effect on BUN levels, while CDDP elevated BUN levels. These results indicate that DWA 2114 represents a second generation platinum antitumor complex.

Animals↗

PubMedDate not supplied

In vitro antitumor activity of a new platinum complex, DWA2114R against human tumor cell lines.

The in vitro antitumor activities of a new platinum complex, (-)-(R)-2-aminomethylpyrrolidine(1,1-cyclobutanedicarboxylato++ +)platinum(II) monohydrate (DWA2114R), against various human tumor lines (23 solid tumor lines and 6 hematopoietic malignant lines) were examined in comparison with those of cis-diammine (1,1-cyclobutanedicarboxylato) platinum(II) (CBDCA) and cis-diamminedichloroplatinum(II) (CDDP). The growth inhibitory activities of the compounds were estimated by MTT assay after the incubation of cells under continuous exposure to the drug. The mean concentrations (microM) of DWA2114R, CBDCA and CDDP needed to inhibit the proliferation of cells by 50% (IC50) were 64.0, 55.1 and 6.8 against solid tumor lines and 8.5, 7.4 and 1.7 against hematopoietic malignant lines, respectively. Comparing the drug sensitivity of the solid tumor lines by type, ovarian cancer was found to be the most susceptible to all three compounds. The susceptibilities of other tumors were in the order prostate, breast and colon cancers for DWA2114R and CBDCA but colon, prostate and breast cancers for CDDP. The correlations of the mean IC50 values for all three combinations of the two compounds were statistically evaluated. A significant correlation was shown between DWA2114R and CBDCA, or CBDCA and CDDP, but not between DWA2114R and CDDP. These results suggest that DWA2114R is almost equivalent in effect to CBDCA which is several times less potent than CDDP, but also that the in vitro cell line subpanel specificity of DWA2114R is in certain respects different from CDDP, in contrast with CBDCA.

Antineoplastic Agents↗

PubMedDate not supplied

Therapeutic potential of humanized anti-interleukin-6 receptor antibody: antitumor activity in xenograft model of multiple myeloma.

A xenograft model of human multiple myeloma (MM) was established in athymic nude mice using S6B45 cells whose growth is dependent on IL-6 in an autocrine fashion. S6B45 cells were inoculated s.c. into mice pretreated with 500 cGy X-ray and anti-asialo GM1 antibody. In more than 90% of the mice, a palpable tumor emerged within 30 days at the inoculation site. Histological observation of the tumor section revealed that the tumor mass was composed of two different phenotypes of myeloma cells, corresponding to plasmablasts and mature plasma cells. I.v. injection of more than 0.125 mg of mouse monoclonal antibody (PM1) against human IL-6R (hIL-6R) on days 1, 3 and 5 markedly delayed the time of tumor incidence. One mg of anti-hIL-6 antibody (MH166) also strongly inhibited the growth of S6B45, whereas control antibody (MOPC31C) and anti-hIL-6R antibody without neutralizing activity (AUK181-6) produced no significant effects. To reduce the antigenicity of PM1 in human, mouse-human chimeric PM1 (chPM1) with human IgG1 constant region and humanized PM1 (hPM1), human IgG1 with mouse complimentarity determining regions, were constructed and evaluated for their in vivo antitumor activity in our model. The in vivo efficacy of these recombinant antibodies (chPM1 and hPM1) was shown to be equivalent to that of the original PM1. These results indicate that the antitumor activity of PM1 is completely recreated in hPM1, and that blocking of the IL-6 signal by this humanized antibody could be a potent therapy for MM.

Animals↗

PubMedDate not supplied

A humanized single-chain Fv fragment with high targeting potential against human malignant gliomas.

A humanized ONS-M21 antibody (hM21) against human medulloblastoma and glioma cells was engineered as a single-chain Fv fragment (scFv), and its ability to internalize into tumor cells was evaluated by conjugation with ricin A. The scFv of hM21 (schM21) was easily purified from E.coli by one-step affinity column chromatography. Purified schM21 bound to a medulloblastoma ONS-76 cell with almost equal antigen-binding activity of hM21-Fab fragment. Furthermore, the schM21-ricin A conjugate inhibited the growth of ONS-76 cells, but not that of antigen-negative hepatoma HuH-7 cells, suggesting that the schM21 can be internalized after binding to antigen-positive cells. Thus, schM21 could be expected to act as a novel carrier of diagnostic and therapeutic agents for brain tumors.

Antibodies, Monoclonal↗