Anti-tumor effects of antibody-alkaline phosphatase conjugates in combination with etoposide phosphate.
Two anti-tumor monoclonal antibodies, L6 (anticarcinoma) and 1F5 (anti-B lymphoma), were covalently linked to alkaline phosphatase (AP), forming conjugates that could bind to the surface of antigen-positive tumor cells. The conjugates were capable of converting a relatively noncytotoxic prodrug, etoposide phosphate (EP), into etoposide--a drug with significant antitumor activity. In vitro studies with a human colon carcinoma cell line, H3347, demonstrated that while EP was less toxic than etoposide by a factor of greater than 100, it was equally toxic when the cells were pretreated with L6-AP, a conjugate that bound to the surface of H3347 cells. The L6-AP conjugate localized in H3347 tumor xenografts in nude mice and histological evaluation indicated that the targeted enzyme (AP) was distributed throughout the tumor mass. A strong antitumor response was observed in H3347-bearing mice that were treated with L6-AP followed 18-24 hr later by EP. This response, which included the rejection of established tumors, was superior to that of EP (P less than 0.005) or etoposide (P less than 0.001) given alone. The IF5-AP conjugate did not bind to H3347 cells and did not enhance the toxicity of EP on these cells in vitro. In addition, IF5-AP did not localize to H3347 tumors in nude mice and did not demonstrate enhanced antitumor activity in combination with the prodrug.
Senter
P D
PD
Oncogen, Seattle, WA 98121.
Saulnier
M G
MG
Schreiber
G J
GJ
Hirschberg
D L
DL
Brown
J P
JP
Hellström
I
I
Hellström
K E
KE
D000469:Alkaline Phosphatase / Q000008:administration & dosage* / Q000378:metabolism; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D001711:Biotransformation; D003110:Colonic Neoplasms / Q000276:immunology / Q000473:pathology; D005047:Etoposide / Q000096:biosynthesis / Q000627:therapeutic use* / Q000633:toxicity; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D011355:Prodrugs / Q000008:administration & dosage / Q000378:metabolism* / Q000633:toxicity; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured / Q000637:transplantation
D000911:Antibodies, Monoclonal; D004364:Pharmaceutical Preparations; D011355:Prodrugs; D005047:Etoposide; D000469:Alkaline Phosphatase