This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Cillo, C. Articles by Hill, R. P. Search for Related Content PubMed PubMed Citation Articles by Cillo, C. Articles by Hill, R. P.

Generation of Drug-resistant Variants in Metastatic B16 Mouse Melanoma Cell Lines¹

Ontario Cancer Institute [C. C., V. L., R. P. H.], Mount Sinai Hospital Research Institute [J. E. D.], and Department of Medical Biophysics [C. C., J. E. D., V. L., R. P. H.], University of Toronto, Toronto, Ontario, Canada M4X 1K9

Genetic instability is recognized as an important aspect of the development of tumor heterogeneity and malignancy. In a previous study [Hill et al. Science (Wash. DC), 244: 998–1001, 1984], we demonstrated that metastatic variants are generated at a more rapid rate in the highly metastatic B16F10 mouse melanoma cell line than in the less metastatic B16F1 cell line. The metastatic variants were phenotypically unstable, being generated and lost at high rates; consequently, we proposed a dynamic heterogeneity model of tumor metastasis which describes these properties quantitatively. As an extension of this work, we have examined the ability of these two melanoma cell lines to generate variants resistant to the drugs methotrexate and N-(phosphonacetyl)-L-aspartate. We observed that the highly metastatic B16F10 cell line generated variants resistant to a given concentration of methotrexate or N-(phosphonacetyl)-L-aspartate at higher rates than the B16F1 cell line. We conclude that B16F10 cells are genetically less stable than B16F1 cells and since resistance to methotrexate and N-(phosphonacetyl)-L-asparate usually results from gene amplification that B16F10 cells possess increased ability to amplify DNA. This higher rate of generation of drug-resistant variants corresponds to the higher rate of generation of metastatic variants we observed previously and suggests that a gene amplification mechanism may be involved in the generation of a metastatic phenotype in B16 melanoma cells.

¹ Supported by the Medical Research Council of Canada, The National Cancer Institute of Canada, and the Ontario Cancer Treatment and Research Foundation.

² Present address: Istituto Internazionale di Genetica e Biofisica, C.P. 3061, 80100 Napoli, Italy.

³ To whom requests for reprints should be addressed, at the Ontario Cancer Institute, 500 Sherbourne Street, Toronto, Ontario, Canada M4X 1K9.

Received 7/ 7/86. Revised 9/18/86. Revised 1/ 2/87. Accepted 2/12/87.

This article has been cited by other articles:

				R. R. Langley and I. J. Fidler Tumor Cell-Organ Microenvironment Interactions in the Pathogenesis of Cancer Metastasis Endocr. Rev., May 1, 2007; 28(3): 297 - 321. [Abstract] [Full Text] [PDF]

				E. M. Amsen, N. Pham, Y. Pak, and D. Rotin The Guanine Nucleotide Exchange Factor CNrasGEF Regulates Melanogenesis and Cell Survival in Melanoma Cells J. Biol. Chem., January 6, 2006; 281(1): 121 - 128. [Abstract] [Full Text] [PDF]

				K. E. Miletti-Gonzalez, S. Chen, N. Muthukumaran, G. N. Saglimbeni, X. Wu, J. Yang, K. Apolito, W. J. Shih, W. N. Hait, and L. Rodriguez-Rodriguez The CD44 Receptor Interacts with P-Glycoprotein to Promote Cell Migration and Invasion in Cancer Cancer Res., August 1, 2005; 65(15): 6660 - 6667. [Abstract] [Full Text] [PDF]

				J.-M. Yang, Z. Xu, H. Wu, H. Zhu, X. Wu, and W. N. Hait Overexpression of Extracellular Matrix Metalloproteinase Inducer in Multidrug Resistant Cancer Cells Mol. Cancer Res., April 1, 2003; 1(6): 420 - 427. [Abstract] [Full Text] [PDF]

				S. Ambs, S. Dennis, J. Fairman, M. Wright, and J. Papkoff Inhibition of Tumor Growth Correlates with the Expression Level of a Human Angiostatin Transgene in Transfected B16F10 Melanoma Cells Cancer Res., November 1, 1999; 59(22): 5773 - 5777. [Abstract] [Full Text] [PDF]

				R. Sutherland Cell and environment interactions in tumor microregions: the multicell spheroid model Science, April 8, 1988; 240(4849): 177 - 184. [Abstract] [PDF]