Cryosurgery is now being used to eradicate a variety of tumors, including t
hose that are found in the kidney. Because it is well known that cancer tre
atments are often most effective when combined with adjunctive therapies, w
e developed a model kidney cell culture system to determine: (1) if 5-fluor
ouracil (5-FU), a compound known to be a poor kidney tumor chemotherapeutic
agent, can be more effective when combined with cryosurgery; and (2) how k
idney cells die through freezing-induced injury that might occur during cry
osurgery. The DNA isolated from kidney cells that died during an exposure t
o -15 degrees C showed nonrandom cleavage when separated on an agarose gel,
indicating that cell death was attributable, in part, to apoptosis, wherea
s DNA isolated from kidney cells that died during exposure to -75 degrees C
showed random cleavage, indicating that cell death was attributable, in pa
rt, to necrosis. The apoptotic protease inhibitor, caspase 1 inhibitor V, w
as able to prevent freezing-induced cell death, supporting the idea that ap
optosis may be a mechanism of cell death in the periphery of the iceball cr
eated by cryosurgical procedures in vivo. Because 5-FU is known to induce a
poptosis, this drug was used in combination with various freezing regimes t
o determine if the combination might be a better method of killing cells th
an either treatment alone. Whereas the addition of 5-FU at the same time or
2 days after freezing resulted in a synergistic lethal effect, many cells
survived this combination treatment. When cells were treated with 5-FU 2 da
ys prior to freezing, however, there was an apparent complete loss of viabi
lity. The reason may be that, by an unknown mechanism, freezing enhances th
e ability of 5-FU-treated cells to move more effectively through the apopto
sis pathway. Kidney tumors may have robust antiapoptotic mechanisms that ma
ke them refractory to 5-FU, but these mechanisms might be overridden by fre
ezing. In either case, the data suggest that chemotherapy may be more effec
tive when followed by cryosurgery.