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Tumor Biology: Use of Tiled Images in Conjunction with Measurements of Cellular Proliferation and Death in Response to Drug Treatments

General Pharmacology, DuPont Pharmaceuticals Co., Wilmington, Delaware 19880-0400 [E. J. W., P. M. C., J. J. D., A. M. S., J. S. K.]; New England Baptist Bone and Joint Institute and Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115 [E. M. G.]; Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts 02115 [J. L.]; and Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213 [M. K. K. W.]

Tumor growth is dependent on the balance between cell proliferation and cell death, and these events occur heterogenously within an individual tumor. We present a methodology that provides integrative information about cell kinetics, cell death, and cell growth within individual tumors in animals treated with cytotoxic chemotherapeutic agents. Using HCT-116 and NCI-H460 cells, human colonic adenocarcinoma and non-small cell lung cells, respectively, traditional xenograft studies were performed. The tumor-bearing animals were treated with cyclophosphamide (Cytoxan), gemcitabine (Gemzar), or mitomycin C, and extensive analysis of the tumors was studied. Cell kinetics were evaluated by measuring the apoptotic and proliferation indices. The ability to image an entire tumor section using "tiling" by creating a large montage from many high-resolution images makes it possible to identify regional differences within areas of tumor and to demonstrate differences in these tumor regions after treatment with selected chemotherapeutic agents. Two specific areas within tumors have been identified: (a) areas of viable cells within the cell cycle, determined by bromodeoxyuridine and/or morphological characteristics determined by hematoxylin staining; and (b) areas of necrosis determined by the absence of bromodeoxyuridine and proliferating cell nuclear antigen-labeled cells coupled with morphological changes. By standardizing the tumor size to 100 mm², different patterns of tumor responses to chemotherapeutic agents were determined. By creating such tiled images and by quantitating cell cycle kinetics, it is possible to gain a more complete understanding of tumor growth and response to treatment, leading to the development of more reliable methods for assessing the clinical behavior of anticancer drugs.

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