E. Kievit et al., DETERMINATION OF TUMOR-RELATED FACTORS OF INFLUENCE ON THE UPTAKE OF THE MONOCLONAL-ANTIBODY 323 A3 IN EXPERIMENTAL HUMAN OVARIAN-CANCER/, International journal of cancer, 71(2), 1997, pp. 237-245
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.