Characterization of a hydroxyurea-resistant human KB cell line with supersensitivity to 6-thioguanine

Yun Yen, Susan P. Grill, Ginger E. Dutschman, Chien Neng Chang, Bing Sen Zhou, Yung Chi Cheng

Research output: Contribution to journalArticle

56 Citations (Scopus)

Abstract

Hydroxyurea (HU) is currently used in the clinic for the treatment of chronic myelogenous leukemia, head and neck carcinoma, and sarcoma. One of its drawbacks, however, is the development of HU resistance. To study this problem, we developed a HU-resistant human KB cell line which exhibits a 15- fold resistance to HU. The characterization of this HU-resistant phenotype revealed a gene amplification of the M2 subunit of ribonucleotide reductase (RR), increased levels of M2 mRNA and protein, and a 3-fold increase of RR activity. This HU-resistant cell line also expressed a 'collateral sensitivity' to 6-thioguanine (6-TG), with a 10-fold decrease in the dose inhibiting cell growth by 50% as compared to the KB parental line. The mechanism responsible for this supersensitivity to 6-TG is believed to be related to an increasingly efficient conversion of 6-TG to its triphosphate form, which is subsequently incorporated into DNA. After passage of the resistant cells in the absence of HU, the cell line reverts. The revertant cells lose their resistance to HU and concomitantly their sensitivity to 6- TG. This phenomenon is due to the return of RR to levels comparable to that of the KB parental cell line. These observations and their relevance to cancer chemotherapy will be discussed in this paper. Our results suggest that a clinical protocol could be designed which would allow for a lower dose of 6-TG to be used by taking advantage of the increased RR activity in HU- refractory cancer patients. Two drugs which display collateral sensitivity are known as a 'Ying-Yang' pair. Alternate treatment with two different Ying- Yang pairs is the rationale for the 'Ying-Yang Ping-Pong' theory in cancer treatment. This rationale allows for effective cancer chemotherapy with reduced toxicity.

Original languageEnglish
Pages (from-to)3686-3691
Number of pages6
JournalCancer Research
Volume54
Issue number14
Publication statusPublished - Jul 15 1994
Externally publishedYes

Fingerprint

Thioguanine
KB Cells
Hydroxyurea
Cell Line
Ribonucleotide Reductases
Neoplasms
Drug Therapy
Gene Amplification
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Clinical Protocols
Sarcoma
Neck
Therapeutics
Head
Carcinoma
Phenotype
Messenger RNA

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Yen, Y., Grill, S. P., Dutschman, G. E., Chang, C. N., Zhou, B. S., & Cheng, Y. C. (1994). Characterization of a hydroxyurea-resistant human KB cell line with supersensitivity to 6-thioguanine. Cancer Research, 54(14), 3686-3691.

Characterization of a hydroxyurea-resistant human KB cell line with supersensitivity to 6-thioguanine. / Yen, Yun; Grill, Susan P.; Dutschman, Ginger E.; Chang, Chien Neng; Zhou, Bing Sen; Cheng, Yung Chi.

In: Cancer Research, Vol. 54, No. 14, 15.07.1994, p. 3686-3691.

Research output: Contribution to journalArticle

Yen, Y, Grill, SP, Dutschman, GE, Chang, CN, Zhou, BS & Cheng, YC 1994, 'Characterization of a hydroxyurea-resistant human KB cell line with supersensitivity to 6-thioguanine', Cancer Research, vol. 54, no. 14, pp. 3686-3691.
Yen Y, Grill SP, Dutschman GE, Chang CN, Zhou BS, Cheng YC. Characterization of a hydroxyurea-resistant human KB cell line with supersensitivity to 6-thioguanine. Cancer Research. 1994 Jul 15;54(14):3686-3691.
Yen, Yun ; Grill, Susan P. ; Dutschman, Ginger E. ; Chang, Chien Neng ; Zhou, Bing Sen ; Cheng, Yung Chi. / Characterization of a hydroxyurea-resistant human KB cell line with supersensitivity to 6-thioguanine. In: Cancer Research. 1994 ; Vol. 54, No. 14. pp. 3686-3691.
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