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Potentiation of Cytotoxicity of 1-ß-D-Arabinofuranosylcytosine for K562 Human Leukemic Cells by Cadeguomycin¹

Institute of Applied Microbiology, University of Tokyo, Tokyo 113, Japan

The treatment of K562 human myeloblastic leukemia cells and YAC-1 murine lymphoma cells with cadeguomycin at concentrations over 0.6 µM significantly enhanced the cytotoxicity of 1-ß-D-arabinofuranosylcytosine (ara-C). The degree of potentiation depended upon the antiblotic concentration. The treatment with 75 µM cadeguomycin for 18 h increased cellular uptake of [³H]ara-C into K562 cells and formation of ara-C nucleotides, as well as incorporation into nucleic acids. The level of the diphosphate of ara-C plus the triphosphate of ara-C was approximately 10 times higher in the cadeguomycin-treated cells than in the untreated cells by 30 min of incubation with [³H]ara-C. The extracts of 15 µM cadeguomycin-treated K562 cells showed increased activity of formation of ara-C nucleotides, resulting in 4- to 5-fold higher formation of the di-and triphosphates of ara-C than the control cell extracts. Cadeguomycin did not significantly change the level of ribonucleotide and deoxyribonu-cleotide pool in K562 cells. The mechanism of potentiation of ara-C by cadeguomycin was discussed.

¹ Supported by a Grant-in-Aid for Cancer Research from the Ministry of Education, Science, and Culture, Japan.

² To whom requests for reprints should be addressed.

³ Present address: National Yang-Ming Medical College, Taipei, Republic of China.

Received 12/13/85. Revised 7/ 1/86. Accepted 10/23/86.