1,25-dihydroxyvitamin D3 increases the sensitivity of human renal carcinoma cells to tumor necrosis factor alpha but not to interferon alpha or lymphokine-activated killer cells.
Renal cell carcinoma is a chemotherapy-resistant tumor which is relatively responsive to immunotherapy. Immunotherapeutic regimes employ interferons or interleukin 2 with or without lymphokine-activated killer cells. Secondary cytokines, induced by interleukin 2 or interferon, may have an important impact on their anti-neoplastic activity. Notable among them is tumor necrosis factor (TNF alpha). We assessed the effect of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) on the susceptibility of the human renal cell carcinoma cell line SK-RC-29 to the cytotoxic and cytostatic actions of TNF alpha, interferon alpha and lymphokine-activated killer cells. Using uptake of the vital dye neutral red as an indicator of viable cell number, we found that addition of 1,25(OH)2D3 (100 nM) to TNF alpha (30 ng/ml)-treated cultures resulted in a 2.6 +/- 0.2-fold (mean +/- S.E.) increase in the cytotoxic effect of the cytokine. The potentiating effect of 1,25(OH)2D3 was dose-dependent, and significant at concentrations equal to or higher than 10 nM. Another dihydroxylated vitamin D metabolite, 24,25(OH)2D3, had no effect on TNF alpha action. The cytotoxic effect of TNF alpha increased whereas the potentiation by 1,25(OH)2D3 decreased with cell density in culture. 1,25(OH)2D3, in contrast to its potentiating effect on TNF alpha action, did not modulate the cytostatic effect of interferon alpha or the susceptibility of SK-RC-29 to killing by lymphokine-activated killer cells. The findings reported here may explain some of the in vivo anti-tumor activity of 1,25(OH)2D3 and provide a rationale for the employment of active vitamin D analogs during immune anti-cancer therapy.
Yacobi
R
R
Department of Physiology and Pharmacology, Tel-Aviv University, Israel.
Koren
R
R
Liberman
U A
UA
Rotem
C
C
Wasserman
L
L
Ravid
A
A
D002117:Calcitriol / Q000494:pharmacology* / Q000627:therapeutic use; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007370:Interferon Type I / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000628:therapy*; D015979:Killer Cells, Lymphokine-Activated / Q000276:immunology*; D011994:Recombinant Proteins; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000627:therapeutic use*
D007370:Interferon Type I; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D002117:Calcitriol