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| ZD2767, an improved system for antibody-directed enzyme prodrug therapy that results in tumor regressions in colorectal tumor xenografts |
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| Author(s): Blakey DC, Burke PJ, Davies DH, Dowell RI, East SJ, Eckersley KP, Fitton JE, McDaid J, Melton RG, NiculescuDuvaz IA, Pinder PE, Sharma SK, Wright AF, Springer CJ |
| Source: CANCER RESEARCH Volume: 56 Issue: 14 Pages: 3287-3292 Published: JUL 15 1996 |
| Times Cited: 41 References: 35 |
| Abstract: ZD2767 represents an improved version of antibody-directed enzyme prodrug therapy. It consists of a conjugate of the F(ab')(2) A5B7 antibody fragment and carboxypeptidase G2 (CPG2) and a prodrug, 4-[N,N-bis(2-iodoethyl)amino]phenoxycarbonyl L-glutamic acid. The IC50 of the prodrug against LoVo colorectal tumor cells was 47 mu M, and cleavage by CPG2 released the potent bis-iodo phenol mustard drug (IC50 = 0.34 mu M). The drug killed both proliferating and quiescent LoVo cells. Administration of the ZD2767 conjugate to nude mice bearing LoVo colorectal xenografts resulted in approximately 1% of injected ZD2767 conjugate localizing/g of tumor after 72 h, and blood and normal tissue levels of the conjugate were 10-50-fold lower. A single round of therapy involving the administration of the prodrug 72 h after the conjugate to athymic mice bearing established LoVo xenografts resulted in approximately 50% of the tumors undergoing complete regressions, tumor growth delays greater than 30 days, and little toxicity (as judged by body-weight loss), Similar studies using a control antibody-CPG2 conjugate that does not bind to LoVo tumor cells resulted in a growth delay of less than 5 days, confirming the tumor specificity of this approach. These studies demonstrate the potential of ZD2767 for the treatment of colorectal cancer. |
| Document Type: Article |
| Language: English |
| Reprint Address: Blakey, DC (reprint author), ZENECA PHARMACEUT, CANC METAB & ENDOCRINE RES DEPT, ALDERLEY PK, MACCLESFIELD SK10 4TG, CHESHIRE ENGLAND |
Addresses:
1. CHARING CROSS HOSP, DEPT MED ONCOL, CRC LABS, LONDON W6 8RF, ENGLAND
2. PUBL HLTH LAB SERV, CTR APPL MICROBIOL & RES, DIV BIOTECHNOL, SALISBURY SP4 0JG, WILTS ENGLAND
3. INST CANC RES, CRC CTR, CANC THERAPEUT INST, SUTTON SM2 5NG, SURREY ENGLAND |
| Publisher: AMER ASSOC CANCER RESEARCH, PUBLIC LEDGER BLDG, SUITE 816, 150 S. INDEPENDENCE MALL W., PHILADELPHIA, PA 19106 |
| Subject Category: Oncology |
| IDS Number: UW674 |
| ISSN: 0008-5472 |
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