|Budget Amount *help
¥2,400,000 (Direct Cost : ¥2,400,000)
Fiscal Year 1992 : ¥700,000 (Direct Cost : ¥700,000)
Fiscal Year 1991 : ¥900,000 (Direct Cost : ¥900,000)
Fiscal Year 1990 : ¥800,000 (Direct Cost : ¥800,000)
Molecular events associated with the transformation into blast crisis phase in Ph^1-positive CML were analyzed. The Southern blot and RT-PCR analyses revealed that no obvious difference between both chronic and crisis phases was observed regarding the breakpoints on bcr gene and the fusional mode of bcr-abl gene. However, blast crisis cells showed the enhanced expression of bcr-abl mRNA, when compared with those of chronic phase cells. By the DNA transfection and PCR analyses, the point-mutational activation of ras oncogene was rarely identified. On the other hand, myeloid crisis cells frequently showed alterations of the p53 anti-oncogene and of its expression. The present study suggested one possibility that a selective and progressive process of Ph^1 clone with high expression of the bcr-abl gene may be involved with the transformation into the myeloid crisis from the chronic phase, and further this progression may be accelerated by the loss of function of anti-oncogene, p53 gene due to the disturbance of a check point on Gl*S entrance.
Consequently, the investigation of a new strategy of bcr/abl oncoprotein-targeted therapeutics was carried out. Antisense oligodeoxynucleotides complementary to bcr-abl mRNA showed no desired antitumor activity, thus indicating that devices of chemical modification and delivery system may bring the future therapeutic application. On the contrary, herbimycin A, an inhibitor of PTK, showed the bcr/abl oncoprotein-targeted antitumor activity on Ph^1-positive leukemia cells and bcr/abl oncogene-transfected cells. These findings were presented in mamuscripts and review articles of English journals.