Enhancement of cytotoxicity of cisplatin in vitro by recombinant human tumor necrosis factor and/or recombinant human interferon-alpha, -beta and -gamma.
This study was conducted to investigate the modulatory effects of recombinant human tumor necrosis factor (rH-TNF) and recombinant human interferon (rH-IFN)-alpha, -beta and -gamma, either alone or in combination, on the cytotoxicity of cisplatin, using MTT assay, against MKN-45 (human stomach adenocarcinoma). MKN-45 was resistant to rH-TNF even at doses up to 10(3) U/ml. rH-IFN-gamma inhibited the survival of MKN-45 dose-dependently, while rH-IFN-alpha and -beta did not inhibit the survival of MKN-45 even at the highest concentrations tested (10(4) U/ml). Combination of rH-TNF with rH-IFN-alpha, -beta or -gamma did not significantly inhibit the survival of MKN-45, except for a combination of 10 U/ml of rH-TNF and 10(3) U/ml of rH-IFN-gamma (P less than 0.05). Cisplatin inhibited the survival of MKN-45 dose-dependently. By the simultaneous combination of cisplatin with rH-TNF and/or rH-IFN-alpha, -beta or -gamma, cytotoxicity of cisplatin was enhanced and the combination effects were additive. The effects of rH-TNF and rH-IFN-alpha, -beta and -gamma on the modification of cytotoxicity of cisplatin were evaluated in terms of modification index (MI), demonstrating that rH-TNF, rH-IFN-alpha, -beta and -gamma all augmented the cytotoxicity of cisplatin: MI values at 10(3) U/ml of rH-IFN-alpha, -beta and -gamma were 1.4, 1.4 and 2.3, respectively; those at the same concentrations of rH-IFN-alpha, -beta and -gamma in the presence of 10 U/ml of rH-TNF were 3.6, 2.5 and 5.1, respectively. These results demonstrating that the cytotoxicity of cisplatin was enhanced by rH-TNF and/or rH-IFN-alpha, -beta or -gamma suggest that cancer may be more effectively treated with the combination of cisplatin with these biological response modifiers than with cisplatin alone.
Kim
C M
CM
Department of Internal Medicine, Korea Cancer Center Hospital, Seoul.
Hong
W S
WS
Lee
J O
JO
Kang
T W
TW
Kim
Y W
YW
Song
J K
JK
Yun
T K
TK
Kim
C Y
CY
D000230:Adenocarcinoma / Q000473:pathology*; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D006801:Humans; D007370:Interferon Type I / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology; D013274:Stomach Neoplasms / Q000473:pathology*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D007370:Interferon Type I; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D002945:Cisplatin