Affiliations: Department of Preventive Medicine, Kyoto Prefectural
University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566,
Japan
Note: [] Department of Preventive Medicine, Kyoto Prefectural University
of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan. Fax: +81
75 241 0792; E-mail: tsakai@basic.kpu-m.ac.jp
Abstract: Recent progress in molecular genetics has facilitated understanding
of the mechanisms of carcinogenesis. However, there is not yet any effective
therapy or prevention for cancer based on the molecular mechanisms of
carcinogenesis. So-called ``gene therapy'' for cancer is expected to become a
new method of treatment, but there are still several serious problems with gene
therapy. As a matter of fact, it seems impossible to adopt gene therapy for
prevention. We therefore tried to develop a different method of cancer
prevention or therapy based on the molecular mechanisms of carcinogenesis. For
instance, the tumor-suppressor gene p53 is mutated in about 50% malignancies.
It is known that p53 stimulates the promoter activities of p21/WAF1, gadd45 and
bax genes, resulting in cell cycle arrest, DNA repair and apoptosis,
respectively. Therefore, chemical compounds that can stimulate these genes
should compensate for the function of p53. As a model of this, we found that
histone deacetylase inhibitors such as butyrate or trichostatin A dramatically
stimulate the p21/WAF1 gene promoter through the Sp1 sites, resulting in cell
cycle arrest. Interestingly, another group has recently reported that
phenylbutyrate, which is also known as a histone deacetylase inhibitor, is very
effective for leukemia patients. We therefore consider methods of up-regulating
p21/WAF, gadd45 or bax genes should be useful for cancer therapy and termed
this method ``Gene-regulating chemotherapy''. Theoretically, the chemicals
up-regulating such genes should be also useful for chemoprevention, and we also
termed it as ``Gene-regulating chemoprevention''. In conclusion, we propose that ``Gene-regulating chemotherapy or
chemoprevention'' may be a promising new method for cancer therapy or
prevention and histone deacetylase inhibitor is a good candidate for this
method.
