SYNERGISTIC EFFECT AND POSSIBLE MECHANISMS OF TUMOR-NECROSIS-FACTOR AND CISPLATIN CYTOTOXICITY UNDER MODERATE HYPERTHERMIA AGAINST GASTRIC-CANCER CELLS
Jf. Buell et al., SYNERGISTIC EFFECT AND POSSIBLE MECHANISMS OF TUMOR-NECROSIS-FACTOR AND CISPLATIN CYTOTOXICITY UNDER MODERATE HYPERTHERMIA AGAINST GASTRIC-CANCER CELLS, Annals of surgical oncology, 4(2), 1997, pp. 141-148
Background: Peritoneal carcinomatosis is a difficult management proble
m, and intraperitoneal treatment approaches may provide an opportunity
to intensify dose and minimize toxicity. The current experiments were
conducted to characterize the cytotoxic effects of cisplatin (cDDP),
tumor necrosis factor (TNF), and hyperthermia (HT) on a gastric cancer
cell line in vitro under conditions achievable with intraperitoneal t
reatment. Methods: Seoul National University gastric cancer cell line
(SNU-5), a poorly differentiated gastric cancer cell line, was tested
for sensitivity to various doses of cDDP, TNF, or combinations of the
two at normothermia (37 degrees C) or HT (42.5 degrees C). The effect
of TNF on cellular rates of cDDP accumulation, efflux, and cDDP-DNA ad
duct formation were evaluated using atomic absorbance spectrometry wit
h Zeemen background correction. Results: During a 2-h exposure to vari
ous doses of cDDP with HT, we observed a supraadditive cytotoxicity of
SNU-5 with 1 to 50 mu g/ml of TNF (p(2) = 0.0001). In the presence of
the three-agent combination (HT, TNF, and cDDP) we observed statistic
ally significant increases in total cellular accumulation of cisplatin
(p(2) = 0.016); a nonsignificant decrease in cellular efflux of drug
(p(2) = 0.098); and a 40% increase in persistent cisplatin DNA damage
as measured by atomic absorption spectrophotometry (p(2) = 0.06). Thes
e patterns were specifically not seen with the combinations of cDDP an
d HT, or cDDP and TNF. Conclusions: These data provide the experimenta
l basis for the use of TNF and cDDP with HT in the treatment of gastri
c cancer and support the investigation of these agents in vivo in the
regional treatment of peritoneal carcinomatosis.