Studies with four different transplantable murine
tumors demonstrated that
surgical instruments contaminated by contact with a
tumor mass could produce
tumors in a
surgical wound. Eighty-seven per cent of mice with
wounds made by invisibly contaminated scissors developed
tumors. Irrigation with water did not prevent
tumor growth. Before spilled
tumor cells can invade and grow into a recurrence in the
wound site, they must first attach to underlying extracellular matrix. We have devised a simple in vitro assay to identify inhibitors of
tumor-cell attachment to develop therapeutic compounds that can prevent
tumor-cell
reimplantation. Various test compounds, including
proteases (
trypsin and
Dispase), known modulators of matrix metabolism (
proline analogues,
cycloheximide,
heparin,
cortisone,
cortexolone, and
heparin-
steroid combinations), large molecular weight
polymers (
agarose,
dextran,
polyethylene oxide), and synthetic
fibronectin peptides were tested for their ability to inhibit mouse
melanoma (B16-F10) cell attachment to gelatinized dishes. Most of these compounds had little or no effect on
tumor-cell adhesion when cells were plated in serum-containing medium. However we identified three compounds that inhibited
tumor-cell attachment in a reversible fashion: (1) a specific inhibitor of
collagen deposition (L-
azetidine-2-carboxylic acid); (2) a
bacterial neutral protease (
Dispase); and (3) synthetic
fibronectin peptides that contained the
arginine-
glycine-asparate (RGD) sequence that is responsible for cell binding.
Dispase and the RGD-containing
peptides also inhibited cell implantation and prevented
tumor formation in a
surgical wound. We propose that inhibitors of attachment might be used either alone or with other
biologic modifiers to prohibit implantation of free
tumor cells at the time of surgery and thus, to prevent local
tumor recurrence.