DETERMINATION OF TUMOR-RELATED FACTORS OF INFLUENCE ON THE UPTAKE OF THE MONOCLONAL-ANTIBODY 323 A3 IN EXPERIMENTAL HUMAN OVARIAN-CANCER/

The epithelial glycoprotein 40 (EGP40) is an important target in the c linic for radioimmunolocalization and monoclonal antibody (MAb)-mediat ed therapy of cancer, We determined which tumor-related factors (inclu ding antigen distribution and density, vascularization and perfusion) were involved in the uptake of the anti-EGP40 MAb 323/A3 in 4 differen t human ovarian cancer xenografts grown s.c. in nude mice, The reactiv ity pattern of 323/A3 in all xenografts in vitro was similar and showe d a strong and homogeneous distribution of the EGP40 antigen. FMa xeno grafts, however, showed the highest uptake of 323/A3 in vivo, which wa s 5.5-, 6.2- and 10.0-fold higher than that in OVCAR-3, Ov.Pe and Ov.S h xenografts, respectively, FMa xenografts contained 2.1- to 3.5-fold more antigen per gram protein when compared with the antigen content o f the other xenografts. FMa and Ov.Sh xenografts demonstrated a better vascularization pattern, whereas Ov.Pe and OVCAR-3 xenografts were mo derately to poorly vascularized. FMa xenografts were also better perfu sed, as was shown by a 1.6- to 1.8-fold higher uptake of the Tc-99m-la beled blood flow marker hexamethylpropyleneamine oxime (HM PAO), The t umor uptake of the non-specific MAb E48 was 2.2- to 11.2-fold lower wh en compared with that of 323/A3, but the sequence of uptake was simila r (FMa > OVCAR-3 = Ov.Pe > Ov.Sh), indicating the lowest extravasation of MAbs in Ov.Sh xenograft tissue, Since both the antigen content and the perfusion appeared to be important factors of influence on the tu mor uptake of 323/A3, attempts were made to manipulate these determina nts to improve the tumor uptake, Neither gamma-interferon nor 5-fluoro uracil were able to increase EGP40 expression in human ovarian cancer cells in vitro, Treatment of tumor-bearing mice with the calcium-antag onist flunarizine did not result in an improved perfusion, although a slight increase in the initial tumor uptake of 323/A3 was observed in Ov.Sh-bearing mice. Our results illustrate the relative contribution o f various tumor-related factors that determine the usefulness of a MAb for imaging and therapy of cancer. (C) 1997 Wiley-Liss, Inc.