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Hydroxyurea Accelerates Loss of Extrachromosomally Amplified Genes from Tumor Cells¹

Division of Oncology, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78284 [D. D. V. H., T. W., B. F., K. D., J. S.], and The Salk Institute for Biological Studies, La Jolla, California 92138 [G. W.]

Gene amplification is one mechanism mediating the resistance of tumor cells to antineoplastic agents and the overexpression of a variety of oncogenes in diverse tumor types. There is mounting evidence that acentric extrachromosomal elements such as double minute chromosomes are common intermediates in the amplification process. These acentric structures partition unequally at mitosis and can be lost in the absence of selection. In the present study, we used human and hamster cell lines documented to contain extrachromosomally amplified drug resistance genes to investigate the feasibility of enhancing the loss rate of the extrachromosomally amplified genes to make the cells more sensitive to drug treatment. The results show that treatment of each of these lines with hydroxyurea accelerates the loss of the extrachromosomally amplified drug resistance genes. Loss of these extrachromosomal genes was associated with a corresponding increase in the drug sensitivity in the cases examined. The mechanism of accelerated loss does not appear to involve a differential effect on the replication of extrachromosomal DNA sequences. The results suggest that hydroxyurea treatment may provide a valuable tool for the general accelerated elimination of extrachromosomally amplified genes.

¹ Supported by research grants from the Bristol Myers Drug Resistance Program (100-R146) (D. V. H.) and the Department of Health and Human Services (Grant U01CA48405) (G. W., D. V. H.), as well as by Medical Oncology Training Grant CA09434 from Department of Health and Human Services (J. S.). Presented in abstract form at the American Association for Cancer Research, May 1990 (46).

² To whom request for reprints should be addressed.

Received 8/ 3/90. Accepted 9/23/91.