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Intrinsic and Extrinsic Heterogeneity in the Responses of Parent and Clonal Human Colon Carcinoma Xenografts to Photon Irradiation¹

Department of Radiation Oncology, Rhode Island Hospital [J. T. L., S. F. B., E. S. L., A. S. G.], and Departments of Radiation Medicine [J. T. L., A. S. G.] and Medicine [D. L. D.], Division of Biology and Medicine, Brown University, Providence, Rhode Island 02912, and Pharmaceuticals Research and Development, Cancer Chemotherapy, E. I. DuPont De Nemours & Co., Inc., Wilmington, Delaware 19898 [D. L. D.]

Responses to photon irradiation of xenografted human colon tumors derived from the heterogeneous DLD-1 line or its derivative A and D subpopulations were determined using excision assay and tumor regrowth delay assays. Differential responses among the three xenografted carcinomas were demonstrated. Clone A tumors treated with up to 17.5 Gy showed no actual regression below pretreatment volume. In contrast, clone D tumors were sensitive to doses as low as 3.5 Gy, and tumor volumes were reduced by 65% with a dose of 17.5 Gy. The responses of DLD-1 tumors were intermediate between the clone A and clone D tumor responses. The survival parameters obtained in the excision assay studies for the DLD-1, clone A, and clone D tumors were, respectively: n = 3.3, 1.4, and 1.0; D₀ (Gy) = 2.1, 2.2, and 2.7; and D_Q (Gy) = 2.6, 0.6, and 0.0. These data indicate that the DLD-1 tumors were the most resistant, with clone A of intermediate sensitivity, clone D being the most sensitive tumor. In addition to the interclonal diversity among xenograft lines, intraclonal variation was also observed with clone A (but not clone D or DLD-1) tumors. A biphasic survival curve of cells from clone A xenografts irradiated in air-breathing hosts clearly indicated a minority (3%) subpopulation of hypoxic cells. Similar results indicating a small percentage of hypoxic cells in clone A solid tumors were obtained from the tumor regrowth delay studies. Also, excision assay data from experiments in which the heterografted carcinomas were irradiated under anoxic conditions support the interpretation that clone A tumors contain a small fraction of hypoxic cells. This study indicates that: (a) heterogeneity in vivo to ionizing radiation exists in the DLD-1 system; and (b) intraclonal variation occurs in vivo due to extrinsic (e.g., environmental hypoxia) factors, such that the intrinsic radioresistance of a subpopulation (clone A) of a heterogeneous human tumor can be further increased.

¹ Supported by USPHS Grants CA 25687, CA 23225, and CA 13943 awarded by the National Cancer Institute, Department of Health and Human Services, and by American Cancer Society Grant PDT 243.

² To whom requests for reprints should be addressed, at Department of Radiation Medicine, Division of Biology and Medicine, Box G, Brown University, Providence, RI 02912.

Received 10/27/83. Accepted 5/25/84.

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