title: A synergistic increase of apoptosis utilizing Fas antigen expression induced by low doses of anticancer drug.
abstract: Anticancer drugs have been known to enhance both Fas receptor and Fas ligand expression on tumor cells. Recently, low doses of cytosine arabinoside (ara-C) were reported to enhance Fas antigen expression in the human myeloid leukemia cell line HL60. Here, we showed that low doses of ara-C (LD-ara-C) and etoposide (LD-VP-16) but not vincristine (LD-VCR) induce Fas expression in the human monocytic leukemia cell line U937. We determined the concentrations of ara-C, VP-16 and VCR as 10, 100 and 1 ng/ml, respectively. The ratios for Fas antigen expression induced in non-treated U937 by 24 h incubations with ara-C, VP-16 or VCR were 1.90, 1.36 and 1.00, respectively. Utilizing the Fas antigen expression induced by low doses of anticancer drugs, we examined whether anti-Fas IgM monoclonal antibody (CH-11) combined with LD-ara-C, LD-VP-16 or LD-VCR enhances apoptosis. When CH-11 and LD-anticancer drug were added simultaneously, the ratios of annexin V positive cells were 67.8 +/- 2.4% with ara-C, 70.0 +/- 1.6% with VP-16 and 54.2 +/- 1.3% with VCR. Thus, the ratios of annexin V positive cells significantly increased when CH-11 was simultaneously added to the cells with ara-C (p < 0.0001) and VP-16 (p < 0.0001), but not with VCP (p = 0.5559), compared with the sums of annexin V positive ratios of CH-11 and LD-anticancer drug added separately. We examined whether a broad-range caspase inhibitor (C.I.) can inhibit the Fas expression enhanced by LD-anticancer drugs. However, the Fas expression enhanced by LD-ara-C or LD-VP-16 was not inhibited by a broad-range caspase inhibitor. We demonstrated that apoptosis induced by LD-ara-C or LD-VP-16 is synergistically increased by the addition of CH-11 in U937.
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D003561:Cytarabine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005047:Etoposide / Q000494:pharmacology*; D006801:Humans; D007075:Immunoglobulin M / Q000494:pharmacology; D013268:Stimulation, Chemical; D020298:U937 Cells; D014750:Vincristine / Q000494:pharmacology*; D019014:fas Receptor / Q000276:immunology / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D007075:Immunoglobulin M; D019014:fas Receptor; D003561:Cytarabine; D014750:Vincristine; D005047:Etoposide