The proteasome inhibitor PS-341 in cancer therapy

The anticancer activity of the boronic acid dipeptide proteasome inhibitor PS-341 was examined in vitro and in vivo. PS-341 was a potent cytotoxic age nt toward MCF-7 human breast carcinoma cells in culture, producing an IC90 of 0.05 mu M on 24 h of exposure to the drug. In the EMT-6 tumor cell survi val assay, PS-341 was equally cytotoxic administered p.o. or by i.p. inject ion up to a dose of 2 mg/kg. PS-341 was also toxic to the bone marrow colon y-forming unit-granulocyte macrophage. PS 341 increased the tumor cell kill ing of radiation therapy, cyclophosphamide, and cisplatin in the EMT-6/Pare nt tumor, but was not able to overcome the in vivo resistance of the EMT-6/ CTX and EMT-6/CDDP tumors. In the tumor grow th delay assay, PS-341 adminis tered p.o. had antitumor activity against the Le,vis lung carcinoma, both p rimary and metastatic disease, In combination, regimens with 5-fluorouracil , cisplatin, Taxol and adriamycin, PS-341 seemed to produce primarily addit ive tumor growth delays against the s.c. tumor and was highly effective aga inst disease metastatic to the lungs. The proteasome is an interesting new target for cancer therapy, and the proteasome inhibitor PS-341 warrants con tinued investigation in cancer therapy.