One of the major obstacles to successful chemotherapeutic treatment of cancer is the
emergence of drug-resistant cancer cells. To try to prevent drug-resistance, anticancer drugs
are frequently used in combination. Research in this laboratory, however, has shown that in
some instances the use of certain drug combinations actually enhances the frequency of
drug-resistant cancer cells. Resistance in these cases comes about by gene amplification.
For example, cancer cells become resistant to N-phosphonoacetyl-L-aspartate (PALA) by
amplification of the gene that codes for the enzyme, aspartate transcarbamoylase, the
target of PALA. Amplification of the gene leads to overproduction of the target enzyme and
PALA-resistance. Pretreatment of cells with cytosine arabinoside (araC) increases the
frequency of PALA-resistance. This laboratory is studying how the resistance occurs and how its
frequency is enhanced by araC. The work is mainly with cultured cells and employs biochemical
and molecular biological techniques.
See Figure.
Recent Publications:
Goz, B., and Bastow, K.F. (1997) A possible role for topoisomerase II in cell death and N-phosphonoacetyl-L-aspartate-resistance frequency and its enhancement by 1--D-arabinofuranosyl cytosine and 5-fluoro-2'-deoxyuridine. Mut Res 38(2)4: 89-106. Abstract
Chen, X., Bastow, K., Goz, B., Kucera, L., Morris-Natschke, S.L., and Ishaq, K.S. (1996) Synthesis, antitumor and antiviral activity of novel thymidine analogs. J Med Chem 39(17): 3412-7. Abstract
Goz, B., and Jeffs, L. (1994) The enhancement of the frequency of resistance to N-phosphonoacetyl-L-aspartate and methotrexate by 1--D-arabinofuranosylcytosine: The effect of dipyridamole. J Pharmacol Exptl Therap 270(2): 480-4. Abstract
Chen, Y., Goz, B., and Kirkman, L. (1993) An analysis of vincristine-resistance in BHK cells pretreated with 1--D- arabinofuranosylcytosine. Anticancer Res 13(1): 249-55. Abstract
