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Pronounced antitumor efficacy of doxorubicin when given as the prodrug DOX‐GA3 in combination with a monoclonal antibody β‐glucuronidase conjugate
Author(s) -
Houba P.H.J.,
Boven E.,
van der MeulenMuileman I.H.,
Leenders R.G.G.,
Scheeren J.W.,
Pinedo H.M.,
Haisma H.J.
Publication year - 2001
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/1097-0215(200002)9999:9999<::aid-ijc1075>3.0.co;2-l
Subject(s) - prodrug , doxorubicin , immunoconjugate , pharmacology , conjugate , monoclonal antibody , therapeutic index , medicine , chemotherapy , chemistry , antibody , drug , immunology , mathematical analysis , mathematics
A glucuronide doxorubicin prodrug N ‐[4‐doxorubicin‐ N ‐carbonyl (oxymethyl) phenyl] O ‐β‐glucuronyl carbamate (DOX‐GA3) has been developed to improve the antitumor effects of doxorubicin (DOX). The prodrug was originally designed to be activated into drug by human β‐glucuronidase (GUS) released from tumor cells in necrotic areas of tumor lesions. The aim of this study was to further improve the antitumor effects of DOX‐GA3 by means of antibody‐directed enzyme prodrug therapy (ADEPT). We thus investigated if the administration of an enzyme‐immunoconjugate prepared from the pancarcinoma Ep‐CAM specific monoclonal antibody (MAb) 323/A3 and β‐glucuronidase would result in improved antitumor effects because of additional enzyme localization in tumor tissue. In vitro, the prodrug DOX‐GA3 was found to be 12‐times less toxic than the parent drug DOX in a human ovarian cancer cell line. Immunospecific and complete activation of the prodrug took place when the cells were pretreated with 323/A3‐β‐glucuronidase conjugate. In nude mice bearing s.c. human ovarian cancer xenografts (FMa) the maximum tolerated dose (MTD) of DOX‐GA3 (500 mg/kg weekly × 2) was much higher when compared with that of DOX (8 mg/kg weekly × 2). In mice bearing well‐established FMa xenografts, the standard treatment of DOX at the MTD (8 mg/kg weekly × 2) resulted in a tumor growth inhibition of 67%. Treatment with DOX‐GA3 at a single dose of 500 mg/kg resulted in a better tumor growth inhibition of 87%. The combination of DOX‐GA3 (500 mg/kg) with 323/A3‐mGUS conjugate and anti‐GUS MAb 105, to clear circulating conjugate, improved the antitumor effect even further to 98%. At the lower dose of 250 mg/kg DOX‐GA3 tumor growth inhibition (34%) was not better than that of DOX. The combination, however, of DOX‐GA3 at 250 mg/kg and 323/A3‐mGUS conjugate plus MAb 105 again greatly improved the antitumor effect (growth inhibition of 93%). DOX given at 8 mg/kg weekly x 2 did not result in tumor regressions. As a result of ADEPT, the number of regressions of tumors improved from 0 out of 12 to 9 out of 11 at a dose of 250 mg/kg DOX‐GA3. At the higher prodrug dose (500 mg/kg) the number of regressions improved from 2 out of 12 to 9 out of 10 as a result from the addition of enzyme‐immunoconjugate. Our studies show that the efficacy of the widely used anti‐cancer agent DOX may be improved by using the prodrug DOX‐GA3, in combination with the tumor‐specific enzyme‐immunoconjugate 323/A3‐mGUS and a conjugate clearing antibody. © 2001 Wiley‐Liss, Inc.