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Evaluation of creatine analogues as a new class of anticancer agents using freshly explanted human tumor cells.

Publication ,  Journal Article
Martin, KJ; Chen, SF; Clark, GM; Degen, D; Wajima, M; Von Hoff, DD; Kaddurah-Daouk, R
Published in: J Natl Cancer Inst
April 20, 1994

BACKGROUND: The creatine kinase (CK) isozymes and their substrates, creatine and creatine phosphate, are believed to play a pivotal role in energy transduction in tissues with large, fluctuating energy demands, such as skeletal muscle, heart, and brain. This enzyme system may also be involved in the process of cellular transformation. Inhibition of tumor cell growth by creatine analogues has been observed and may be due to the ability of these analogues to impair cellular energy generation and utilization. PURPOSE: An in vitro human tumor colony-forming assay was used to predict the clinical usefulness of creatine analogues as anticancer agents. METHODS: The ability of cyclocreatine (1-carboxymethyl-2-iminoimidazolidine) and homocyclocreatine (1-carboxyethyl-2-iminoimidazolidine) to inhibit the growth of cells prepared from tumor samples taken directly from patients was evaluated by quantitative measurement of colony formation in a soft-agar cell culture assay system. Cyclocreatine was tested in this human tumor colony-forming assay at concentrations ranging from 0.067 to 20 mM against 128 tumor samples, 51 of which formed colonies in the assay and were considered evaluable. Homocyclocreatine was similarly tested at concentrations from 0.2 to 20 mM against 139 tumor samples; 54 were considered evaluable. The colony-forming assay was also used to compare the efficacy of the creatine analogues to representatives from the six major classes of standard chemotherapeutics (alkylating agents, antimetabolites, DNA intercalators, platinum compounds, topoisomerase inhibitors, and tubulin-interacting agents). In addition, CK levels were measured in 192 tumor samples that were taken from 166 patients. RESULTS: Cyclocreatine and homocyclocreatine, at concentrations previously achieved in animal tissues (7-20 mM), had antitumor activity against 19% and 50%, respectively, of tumor samples that formed colonies in the assay. Cyclocreatine was effective against a subset of tumors sensitive to homocyclocreatine (P = .023; Fisher's exact test), which was the more potent creatine analogue in this assay (P < .001; McNemar's test). No relationships were seen between tumor samples sensitive to the creatine analogues and those sensitive to standard chemotherapeutics. Pairwise Wilcoxon rank sum tests indicated that CK activity was significantly higher in tumors with any growth in the colony assay compared with tumors that did not grow (P < .025). CONCLUSIONS: The creatine analogues, cyclocreatine and homocyclocreatine, effectively reduced colony formation of freshly explanted human tumor cells. The mechanism of action or resistance to these compounds seems to differ from those of standard chemotherapeutics. IMPLICATIONS: Creatine analogues that may alter the energy status of the tumor cell potentially represent promising new anticancer agents that function through a unique mechanism.

Duke Scholars

Published In

J Natl Cancer Inst

DOI

ISSN

0027-8874

Publication Date

April 20, 1994

Volume

86

Issue

8

Start / End Page

608 / 613

Location

United States

Related Subject Headings

  • Tumor Stem Cell Assay
  • Tumor Cells, Cultured
  • Predictive Value of Tests
  • Oncology & Carcinogenesis
  • Imidazolidines
  • Humans
  • Creatinine
  • Antineoplastic Agents
  • 3211 Oncology and carcinogenesis
  • 1112 Oncology and Carcinogenesis
 

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Martin, K. J., Chen, S. F., Clark, G. M., Degen, D., Wajima, M., Von Hoff, D. D., & Kaddurah-Daouk, R. (1994). Evaluation of creatine analogues as a new class of anticancer agents using freshly explanted human tumor cells. J Natl Cancer Inst, 86(8), 608–613. https://doi.org/10.1093/jnci/86.8.608
Martin, K. J., S. F. Chen, G. M. Clark, D. Degen, M. Wajima, D. D. Von Hoff, and R. Kaddurah-Daouk. “Evaluation of creatine analogues as a new class of anticancer agents using freshly explanted human tumor cells.J Natl Cancer Inst 86, no. 8 (April 20, 1994): 608–13. https://doi.org/10.1093/jnci/86.8.608.
Martin KJ, Chen SF, Clark GM, Degen D, Wajima M, Von Hoff DD, et al. Evaluation of creatine analogues as a new class of anticancer agents using freshly explanted human tumor cells. J Natl Cancer Inst. 1994 Apr 20;86(8):608–13.
Martin, K. J., et al. “Evaluation of creatine analogues as a new class of anticancer agents using freshly explanted human tumor cells.J Natl Cancer Inst, vol. 86, no. 8, Apr. 1994, pp. 608–13. Pubmed, doi:10.1093/jnci/86.8.608.
Martin KJ, Chen SF, Clark GM, Degen D, Wajima M, Von Hoff DD, Kaddurah-Daouk R. Evaluation of creatine analogues as a new class of anticancer agents using freshly explanted human tumor cells. J Natl Cancer Inst. 1994 Apr 20;86(8):608–613.
Journal cover image

Published In

J Natl Cancer Inst

DOI

ISSN

0027-8874

Publication Date

April 20, 1994

Volume

86

Issue

8

Start / End Page

608 / 613

Location

United States

Related Subject Headings

  • Tumor Stem Cell Assay
  • Tumor Cells, Cultured
  • Predictive Value of Tests
  • Oncology & Carcinogenesis
  • Imidazolidines
  • Humans
  • Creatinine
  • Antineoplastic Agents
  • 3211 Oncology and carcinogenesis
  • 1112 Oncology and Carcinogenesis