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标题：Biological Properties of Conjugates of Mitomycin C with Estradiol Benzoate and Estradiol : Their Stability Characteristics in Biological Media and Their Binding Abilities to Estrogen Receptor
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作者：Nobuyuki ISHIKI ; Hiraku ONISHI ; Yoshiharu MACHIDA 等
期刊名称：Biological and Pharmaceutical Bulletin
印刷版ISSN：0918-6158
电子版ISSN：1347-5215
出版年度：1997
卷号：20
期号：10
页码：1096-1102
DOI：10.1248/bpb.20.1096
出版社：The Pharmaceutical Society of Japan
摘要：Conjugates of mitomycin C (MMC) with estradiol benzoate and estradiol via glutaric acid, abbreviated to EB-glu-MMC and E-glu-MMC, respectively, were investigated in vitro to determine their stability and MMC regeneration properties in biological media and on their binding to estrogen receptor. EB-glu-MMC and E-glu-MMC were added into a mixture of 1/15 M phosphate buffer, pH 7.4, (ionic strength=0.3), propylene glycol (PG) and rat plasma (4 : 5 : 1, v/v/v), named 10% plasma, or into a mixture of the buffer, PG and rat liver homogenate (9 : 10 : 1, v/v/w), named 5% liver homogenate, and each was incubated at 37°C. The conversion characteristics of EB-glu-MMC and E-glu-MMC were compared with those in the buffer-PG (1 : 1, v/v) mixture previously reported. In 10% plasma, the change of EB-glu-MMC to E-glu-MMC was accelerated enzymatically to some extent, while the enzymatic degradation of E-glu-MMC was not accelerated at all. In 5% liver homogenate, EB-glu-MMC changed quickly to E-glu-MMC, whereas the degradation of E-glu-MMC was accelerated very little. E-glu-MMC was considered to be rather stable against enzyme in the biological media. Competitive binding studies using the rat uterine estrogen receptor showed that the specific binding affinity of E-glu-MMC was 0.81% to that of estradiol, while E-glu-MMC hardly exhibited specific binding. E-glu-MMC was regarded as a hormone-drug conjugate showing a small specific binding affinity to the estrogen receptor. E-glu-MMC is considered to be an effective antitumor agent which gradually generates MMC in the body, and its receptor-mediated action to target cells such as estrogen receptor-positive tumor cells might be possible.
关键词：hormone-drug conjugate;mitomycin C;estradiol;estradiol benzoate;biological media;estrogen receptor