Intratumoral generation of 5-fluorouracil mediated by an antibody-cytosine deaminase conjugate in combination with 5-fluorocytosine.
Cytosine deaminase (CD) is a microbial enzyme that can convert the antifungal agent 5-fluorocytosine (5-FC) into the antitumor agent, 5-fluorouracil (5-FU). The enzyme was chemically conjugated to the L6 monoclonal antibody, forming a conjugate that bound to antigens on the H2981 lung adenocarcinoma. Detailed studies were undertaken to determine the extent to which L6-CD generated 5-FU in tumor-bearing mice. Very high tumor:blood ratios of L6-CD (42:1) in vivo were obtained by injecting the conjugate followed 24 h later by an antiidiotypic antibody that could bind to circulating L6-CD but not to L6-CD that was bound to H2981 cells. As a result, significantly more 5-FC could be administered (> 800 mg/kg) than 5-FU (90 mg/kg). L6-CD converted 5-FC into 5-FU such that the L6-CD/antiidiotypic monoclonal antibody/5-FC combination resulted in 17 times more intratumoral 5-FU compared to systemic 5-FU administration. The conversion was antigen dependent since much lower intratumoral 5-FU levels were obtained in H3719 tumors that failed to localize L6-CD. The conversion of 5-FC into 5-FU was low in blood, kidneys, and liver. This demonstrates that a major increase in intratumoral drug concentrations can be attained with an monoclonal antibody-enzyme conjugate in combination with an anticancer prodrug compared to systemic drug therapy.
Wallace
P M
PM
Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, Washington 98121.
MacMaster
J F
JF
Smith
V F
VF
Kerr
D E
DE
Senter
P D
PD
Cosand
W L
WL
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D043525:Cytosine Deaminase; D005260:Female; D005437:Flucytosine / Q000378:metabolism* / Q000493:pharmacokinetics; D005472:Fluorouracil / Q000378:metabolism* / Q000493:pharmacokinetics; D051379:Mice; D008819:Mice, Nude; D009700:Nucleoside Deaminases / Q000378:metabolism / Q000494:pharmacology*; D011355:Prodrugs / Q000378:metabolism*; D014018:Tissue Distribution
D000911:Antibodies, Monoclonal; D011355:Prodrugs; D005437:Flucytosine; D009700:Nucleoside Deaminases; D043525:Cytosine Deaminase; D005472:Fluorouracil