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.

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 degrees 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 EB-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.