Ablation of human choriocarcinoma xenografts in nude mice by antibody-directed enzyme prodrug therapy (ADEPT) with three novel compounds.
Three novel prodrugs have been designed for use as anticancer agents. Each is a bifunctional alkylating agent which has been protected to form a relatively inactive prodrug. They are designed to be activated to their corresponding alkylating agents at a tumour site by prior administration of an antitumour antibody conjugated to the bacterial enzyme carboxypeptidase G2 (CPG2) in a two-phase system called antibody-directed enzyme prodrug therapy (ADEPT). The Km and Vmax values for three different antibody-CPG2 conjugates were determined in relation to each prodrug. The Km values ranged from 4.5-12 mumol/l and the Vmax from 0.5-1.6 mumol/U/min. Athymic Nu/Nu mice with palpable transplanted human choriocarcinoma xenografts, which are resistant to conventional chemotherapy, were treated with anti-human chorionic gonadotropin antibodies conjugated to CPG2. This was followed by each of the three novel prodrugs. Significant increase in survival was obtained in three of the regimens tested using only one course of treatment. This demonstrates the potential of a tumour-localised bacterial enzyme to activate protected alkylating agents in order to eradicate an established human xenograft.
Springer
C J
CJ
Department of Medical Oncology, Charing Cross Hospital, London, U.K.
Bagshawe
K D
KD
Sharma
S K
SK
Searle
F
F
Boden
J A
JA
Antoniw
P
P
Burke
P J
PJ
Rogers
G T
GT
Sherwood
R F
RF
Melton
R G
RG
D000477:Alkylating Agents / Q000627:therapeutic use; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002822:Choriocarcinoma / Q000188:drug therapy* / Q000401:mortality; D006063:Chorionic Gonadotropin / Q000276:immunology; D004337:Drug Carriers; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011355:Prodrugs / Q000627:therapeutic use*; D014183:Transplantation, Heterologous; D011623:gamma-Glutamyl Hydrolase / Q000008:administration & dosage*
D000477:Alkylating Agents; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D006063:Chorionic Gonadotropin; D004337:Drug Carriers; D011355:Prodrugs; D011623:gamma-Glutamyl Hydrolase