The OVC-8 human ovarian cancer cell line constitutively expresses tumor necrosis factor alpha (TNF-alpha) mRNA and protein and is resistant to TNF-alpha. When OVC-8 cells are treated with pentoxifylline (PTX), the level of mRNA for TNF-alpha is markedly reduced. Combination treatment of OVC-8 cells with PTX and TNF-alpha overcomes the resistance. PTX-treatment has no effect on the expression of TNF-alpha mRNA in C30 cells, which do not constitutively express TNF-alpha mRNA. The combination of PTX and TNF-alpha do not overcome the resistance of C30 cells to TNF-alpha. PTX or anti-TNF-alpha monoclonal antibody has no effect on the growth of OVC-8 cells, suggesting that the growth of OVC-8 cells does not depend upon an autocrine action of TNF-alpha. The synergistic cytotoxic effect obtained with ovarian cancer cells suggests that the combination of PTX and TNF-alpha could be applied clinically in the therapy of TNF-alpha-producing ovarian cancer.

Antibodies, Monoclonal↗

PubMedDate not supplied

Actinomycin D and gemcitabine synergistically sensitize androgen-independent prostate cancer cells to Apo2L/TRAIL-mediated apoptosis.

The cytotoxic efficacy and kinetics involved in sensitization of Apo2L/TRAIL-resistant, androgen-independent prostate cancer cells to Apo2L/TRAIL or tumor necrosis factor-alpha or Fas ligand-mediated apoptosis were tested using subclinical concentrations of actinomycin D, paclitaxel, cisplatinum, gemcitabine, and radiation in CL-1, LNCaP, DU-145, and PC3 prostate cancer cell lines. CL-1 cells expressed all four Apo2L/TRAIL receptors and were resistant to Apo2L/TRAIL-mediated apoptosis (1-5,000 ng/mL) and to the sensitizers when given alone. Pretreatment with actinomycin D followed by Apo2L/TRAIL or tumor necrosis factor-alpha or anti-Fas CH-11 monoclonal antibody, but not in the reverse order, induced apoptosis in all cell lines. Synergistic sensitization in CL-1 cells was shown also with gemcitabine but not with cisplatinum, VP-16, paclitaxel, or radiation. Incubating the Apo2L/TRAIL-resistant CL-1, LNCaP, DU-145, and PC3 cell lines with 100 ng/mL actinomycin D for 4 hours followed by Apo2L/TRAIL for 24 hours resulted in 45.4 +/- 10.3%, 58.8 +/- 3.6%, 53.4 +/- 1.4%, and 84.2 +/- 8.4% apoptosis, respectively. Prolonging the sensitization time to 24 hours followed by 20 hours of incubation with Apo2L/TRAIL further enhanced the killing activity against CL-1 cells to 89 +/- 1% (delta = 60%, synergistic ratio = 3.1). This killing has a biphasic pattern that was contributed to by apoptosis (83%) and necrosis (17%) at 10 hours (peak) and 40% and 60%, respectively, at 20 hours. These results suggest that prostate cancer cells' resistance to Apo2L/TRAIL-mediated apoptosis can be reversed and synergy is achieved by sensitization of tumor cells with subclinical concentrations of actinomycin D or gemcitabine and may be useful clinically for the treatment of metastatic hormone- and drug-refractory prostate cancer.

Androgens↗