Soo Kie Kim

A concise synthesis and in vitro cytotoxicity of new labdane diterpenes

A new series of labdane-related diterpenes have been synthesized from (-)-sclareol and assayed in vitro cytotoxicity against mouse and human cancer cells. A key intermediate, homodrimane and furanolabdane derivatives show good in vitro cytotoxicity comparable to those of mitomycin C and adriamycin.

Radiation treatment in patients with recurrent Kimura's disease

PURPOSE To assess the benefits of radiotherapy for patients with recurrent Kimuras disease and to document the role of radiation treatment as a successful mode of therapy. METHODS AND MATERIALS From 1985 to 1991, a total of 26 patients with Kimuras disease were treated by local excision and/or systemic steroids at Yonsei University, Yonsei Cancer Center Hospital. Seventeen patients among them eventually had local recurrence after surgical excision. The 17 patients with recurrent Kimuras disease were divided into two groups on the basis of those who received radiation treatment and those who did not. Eight patients in the nonradiation group were treated by systemic steroids alone with individualized doses and schedules. The remaining nine patients in the radiation group were treated by external beam irradiation. The prescribed radiation doses varied from 21.6 to 45 Gy. A comparative analysis on treatment results between both groups was undertaken retrospectively. RESULTS The majority of the recurrent cases in the nonradiation group treated by steroids alone experienced rapid rerecurrence of the disease. In contrast, all of the patients except one case in the radiation group achieved excellent local control with moderate doses of radiation. There was a significant difference in the rerecurrence rate between the patients of the radiation group (11%) and the nonradiation group (75%). No clear dose-response relationship could be derived from the patients of the radiation group. No secondary malignancies in the irradiated areas have been observed. CONCLUSION Our results suggest that radiation treatment is preferable as an alternative option for patients with recurrent Kimuras disease who have failed to achieve local control by other modalities.

A new antitumor agent: methyl sulfonium perchlorate of echinomycin.

Newly modified-echinomycin such as S-methylated sulfonium perchlorate of echinomycin (1), monosulfoxide (2), disulfoxid (3) and sulfone (4) have been prepared and evaluated for in vitro biological activities of cytotoxicity against P388, B16 and SNU-16 as well as in vivo antitumor activity against murine leukemia P388 and melanoma B16.

Synthesis of 6-aziridlnylbenzimidazole derivatives and theirin vitro antitumor activities

In search for new antitumor agents, twelve 6-aziridinylbenzimidazole derivatives were synthesized and their cytotoxicities were tested against three cancer cell lines (mouse lymphocytic leukemia P388 and B16, and human gastric carcinoma SNU-16). From 4-amino-3-nitrotoluene as the starting material, 2-(acetoxymethyl)benzimidazoles (5a–d) were obtained by Phillips reaction. These benzimidazoles were then reacted with Fremys salt to give a mixture of three 2-(acetoxymethyl) (8a–c) and four 2-(hydroxymethyl)benzimidazole-4,7-diones (9a–d). Addition of these quinones with aziridine afforded 6-aziridinyl-2-(acetoxymethyl) (10a–c) and 6-aziridinyl-2-(hydroxymethyl)benzimidazole-4,7-diones (11a–d). Utilizing 2-(hydroxymethyl)benzimidazole-4,7-diones (9b,d), esters10d and13e–h were prepared by the sequential reactions of esterification and addition. The synthesized compounds show potent cytotoxicity against all of three cell lines tested. The cytotoxicities of10a–d or11a–d against SNU-16 were superior to those of13e–h, and were equal to or slightly higher than that of mitomycin C. Compounds11a–d were slightly more cytotoxic than10a–d in all cell lines tested.

Limited Effect of CpG ODN in Preventing Type 1 Diabetes in NOD Mice

Type 1 diabetes is considered as Th1 cell mediated autoimmune disease and the suppression of Th1 cells or the activation of Th2 cells has been regarded as a plausible immunologic intervention for the prevention of type 1 diabetogenesis in a rodent model. CpG ODN is an immunostimulatory sequence primarily present in bacterial DNA, viral DNA and BCG. CpG ODN is conventionally classified as a Th1 cell activator, which has been clinically applied to cancer, allergy and infectious disease. Recently, there was a promising report of that CpG ODN administration suppressed the development of type 1 diabetes in NOD mice by inducing Th2 cell mediated cytokine. However, the antidiabetogenic effect of CpG ODN on NOD mice is controversial. Thus, two studies were serially undertaken with various kinds of CpG motif to find a more optimal sequence and administration method. In the first study, CpG ODN was vaccinated four times and pancreatic inflammation and the quantity of serum insulin subsequently evaluated. In the second study, the amounts of IFN γ and IL-4 in sera were measured as representative cytokines of Th1 and Th2 cells, respectively. As a result, vaccination or continuous injection of CpG ODN failed to show a preventive effect on type 1 diabetogenesis in NOD mice. Structural differences of CpG ODN also had no affect on the result. CpG ODN also consistently showed affect on the pancreatic pathology. The productions of IFN and IL-4 were γ detected only in the K and D type CpG ODN administration groups. Comparison of the two cytokines leads to the conclusion that CpG ODN generated a Th1-weighted response in both study groups. It was assumed that CpG ODN failed to produce Th2-weighted cytokine milieu, which can overcome the genetically determined phenotype of NOD mice. Given these results, it was concluded that the immunotherapeutic application of CpG ODN on Type 1 diabetes had clear limitations.

Synthesis andin vitro antitumor activity of isoazamitosene and isoiminoazamitosene derivatives

Seven isoazamitosene derivatives, mitomycin analogues, were synthesized and tested for cytotoxicities against leukemia and gastric cancer cell lines. Preparation of a pyrrolo[1,2-a]benzimidazole (3) (azamitosene ring system) was completed by utilizing the Lewis acid-catalized cyclization, witho-chloronitrotoluene as the starting material. Nitration of3 produced a mixture of two isomers (5-nitro isomer (4) and 7-nitro isomer (5)) in product ratio of 36∶52.4 was directly converted into quinone (7) by reduction and Fremy oxidaton. Finally, quinone derivatives (8, 9, 10, and11) were synthesized by 1,4-addition of7 with cyclic secondary amines. From above-mentioned5, 8-nitro compound (15) was prepared in 4 steps. At pH 3, Fremy oxidation of15 produced quinone (16), whereas iminoquinone derivatives (17a and17b) at pH 7. Isoazamitosene derivatives (8, 9, 10, and11), containing cyclic amino groups at the 7-position, showed potent cytotoxicity on P388, SNU-1, and KHH tumor cell lines. Among them,8 had stronger cytotoxicity against SNU-1 cell line than mitomycin and adriamycin. Considering these results, isoazamitosene derivatives may had unique cytotoxicity profiles. However, isoiminoazamitosene derivatives (17a and17b) revealed very weak cytotoxicity.

In Vitro chemosensitivity test of SK-302B on human colon carcinoma cell lines

SK-302B, an antibiotic purified from soilStreptomyces sp. 302, was structurally identified as echinomycin (C50H66N11S2). In the present experiment, the possibility of SK-302B as an anticolon cancer agent was investigated by using chemosensitivity system (MTT assay, clonogenic assay). Treatment of SK-302B on various colon cancer cell lines resulted in a significant cytotoxicity and tumor colony formation inhibition. These studies showed that SK-302B had a potent inhibition on colon cancer cells.