Atrimustine

Cyclosporin A (CsA) inhibited interleukin 2 (IL-2), IL-3, interferon gamma (IFN gamma), GM-CSF and tumor necrosis factor alpha (TNF alpha) mRNA expression in spleen cells stimulated with concavalin A (Con A) when determined by the semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) method. FK506 which has a similar immunosuppressive mechanism to that of CsA also showed the same inhibitory effects except for decreased IL-5 and IL-6 mRNA expression. In contrast, both CsA and FK506 enhanced transforming growth factor beta (TGF beta) and IL-1 beta mRNA expression. Another immunosuppressant KM2210 did not show any inhibitory effects on cytokine gene expression but rather enhanced IL-10, IL-6, TGF beta and IL-1 mRNA expression, thus suggesting that KM2210 has a completely different immunosuppressive mechanism from that of CsA and FK506. Anti-TFG beta 1 antibody abrogated the suppression by KM2210 of BALB/c anti-3H/He mixed lymphocyte reaction (MLR) whereas this antibody did not abrogate the suppression by CsA and FK506 of BALB/c anti-C3H/He MLR. These results indicate that TGF beta is one of the major cytokines in KM2210 immunosuppression, in addition to IL-10, but not in immunosuppression by CsA and FK506.

It is known that diffusible trophic factors play an important role in both the normal and cancerous growth regulatory processes of hormone‐responsive cells such as are found in the prostate and mammary glands. Consequently, it is important to identify whether the production of such growth factors is affected by administration of therapeutic agents. We examined the effect of bestrabucil, a benzoate of an estradiol‐chlorambucil conjugate, on the production of growth factor(s) by Shionogi carcinoma 115 (SC‐115) cells, an androgen‐responsive cultured cancer cell line. We then investigated whether the inhibitory effect found was specific to bestrabucil, or if it was also produced by a mixture of the 2 compounds, estradiol and chlorambucil. Bioassay employing BALB/3T3 cells demonstrated the presence of two kinds of growth factor in the conditioned medium obtained by culturing SC‐115 cells in medium containing 10‐8 M testosterone; these factors could be separated by heparin‐sepharose column chromatography using 0.5 M NaCI and 1.1 M NaCI. When the SC‐115 cells were cultured in medium containing bestrabucil, at a concentration of 10−5 M, no growth factor activity was detected in the fraction eluted from the heparin‐sepharose column by 1.1 M NaCI. At bestrabucil concentrations of 105‐107 M, concentration‐dependent inhibition of growth factor production by SC‐115 cells could be demonstrated by 3H‐thymidine uptake assay. However, this inhibitory effect could not be demonstrated using only a mixture of estradiol and chlorambucil. The finding that bestrabucil specifically inhibits the production of growth factor(s) may help in the development of a new class of drugs which will be clinically useful in treating hormone‐responsive cancer.