Enhancement of the in vitro and in vivo antitumor activities of phosphorylated mitomycin C and etoposide derivatives by monoclonal antibody-alkaline phosphatase conjugates.
Alkaline phosphatase (AP) was covalently linked to the two antitumor monoclonal antibodies, L6 (anticarcinoma) and 1F5 (anti-B lymphoma), forming conjugates that could bind to antigen-positive tumor cells. The conjugates were able to convert the prodrugs, mitomycin phosphate (MOP) and etoposide phosphate (EP), into an active mitomycin C derivative, mitomycin alcohol, and etoposide, respectively. MOP and EP were less toxic to cultured cells from the H2981 lung adenocarcinoma than their respective hydrolysis products, mitomycin alcohol and etoposide, by a factor greater than 100, and they were also less toxic in mice. Pretreatment of H2981 cells with L6-AP greatly enhanced the cytotoxic effects of MOP and EP, while 1F5-AP caused no such enhancement. A strong antitumor response was observed in H2981-bearing mice that were treated with L6-AP followed 24 h later by either MOP or a combination of MOP and EP. This response was superior to that of MOP or combinations of MOP and EP given alone.
Senter
P D
PD
Oncogen, Seattle, Washington 98121.
Schreiber
G J
GJ
Hirschberg
D L
DL
Ashe
S A
SA
Hellström
K E
KE
Hellström
I
I
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000469:Alkaline Phosphatase / Q000378:metabolism / Q000627:therapeutic use*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D001711:Biotransformation; D005047:Etoposide / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D008937:Mitomycins / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D009368:Neoplasm Transplantation; D009943:Organophosphorus Compounds; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured / Q000166:cytology* / Q000187:drug effects
D000911:Antibodies, Monoclonal; D008937:Mitomycins; D009943:Organophosphorus Compounds; C061399:mitomycin phosphate; C061400:etoposide phosphate; D005047:Etoposide; D000469:Alkaline Phosphatase