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 agent toward MCF-7 human breast carcinoma cells in culture, producing an IC90 of 0.05 microM on 24 h of exposure to the drug. In the EMT-6 tumor cell survival assay, PS-341 was equally cytotoxic administered p.o. or by i.p. injection up to a dose of 2 mg/kg. PS-341 was also toxic to the bone marrow colony-forming unit-granulocyte macrophage. PS-341 increased the tumor cell killing of radiation therapy, cyclophosphamide, and cisplatin in the EMT-6/Parent tumor, but was not able to overcome the in vivo resistance of the EMT-6/CTX and EMT-6/CDDP tumors. In the tumor growth delay assay, PS-341 administered p.o. had antitumor activity against the Lewis lung carcinoma, both primary and metastatic disease. In combination, regimens with 5-fluorouracil, cisplatin, Taxol and adriamycin, PS-341 seemed to produce primarily additive tumor growth delays against the s.c. tumor and was highly effective against disease metastatic to the lungs. The proteasome is an interesting new target for cancer therapy, and the proteasome inhibitor PS-341 warrants continued investigation in cancer therapy.
Teicher
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BA
Dana-Farber Cancer Institute and Joint Center for Radiation Therapy, Boston, Massachusetts 02115, USA. TEICHER_BEVERLY_A@LILLY.COM
Ara
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Herbst
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Palombella
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VJ
Adams
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D000230:Adenocarcinoma / Q000188:drug therapy* / Q000532:radiotherapy; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D001897:Boronic Acids / Q000378:metabolism / Q000494:pharmacology*; D000069286:Bortezomib; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy; D002945:Cisplatin / Q000008:administration & dosage; D003520:Cyclophosphamide / Q000008:administration & dosage; D004151:Dipeptides / Q000494:pharmacology*; D004357:Drug Synergism; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000532:radiotherapy; D051379:Mice; D008807:Mice, Inbred BALB C; D011480:Protease Inhibitors / Q000494:pharmacology*; D011719:Pyrazines / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014452:Ubiquitins / Q000378:metabolism
D000970:Antineoplastic Agents; D001897:Boronic Acids; D004151:Dipeptides; D011480:Protease Inhibitors; D011719:Pyrazines; D011838:Radiation-Sensitizing Agents; D014452:Ubiquitins; D000069286:Bortezomib; D003520:Cyclophosphamide; D002945:Cisplatin