Abstract: Purpose: We seek to determine whether cellular radiosensitivity in nineteen human colorectal tumor cell lines and three human glioblastoma tumor cell lines segregate into statistically distinct groups and whether such groups correlate with gene expression. Methods: We measure clonogenic survival in 22 cell lines that vary in radiosensitivity and in expression of selected genes: ATM, TP53, CDKN1A, 14-3-3σ, Ki-ras and DNA mismatch repair genes. We describe and compare radiosensitivity in these cell lines by one-parameter or two parameter analysis. Results: Radiosensitivity varies among and between colorectal tumor cell lines and glioblastoma cell lines. When compared directly using survival, or using two-parameter analysis of radiosensitivity, cell lines distribute into four statistically-significant radiosensitivity groups. These groups associate strongly with the status of two genes, ATM and TP53, but do not associate with CDKN1A, 14-3-3σ, Ki-ras and DNA mismatch repair genes. Conclusions: Intrinsic cellular radiosensitivity of 22 colorectal and glioblastoma cell lines fall into four radiosensitivity groups that associate with expression of ATM and TP53. These analyses suggest multiple mechanisms underlay intrinsic cellular radiosensitivity.

Abstract We test the hypothesis that a pulse of the anti-cancer agent doxorubicin renders cells more sensitive to ionizing radiation in a strongly time-specific, dose-specific manner. We have treated cultured cells from a human tumor line, HepG2, with graded doses of two agents: doxorubicin (Dox) and ionizing radiation (XR), delivered in sequence-specific, time-specific, dose-specific patterns. We observe a strong increase in cell killing, up to 120 fold, between pulsed treatment with Dox followed exactly 4 hours later with acute XR. This effect is more pronounced for larger doses of irradiation ( ��/7.5 Gy). These data demonstrate proof of principal in a model system that timing between agents may be an exceptionally important variable in using combined, multi-modal therapy in the treatment of cancer. Since the levels of Dox needed to induce substantial increases in cellular radiosensitivity may be achievable in vivo, we suggest that this phenomenon, which we refer to as time-targeted therapy (TTT), be considered for translation into the clinic if preclinical studies identify appropriate timing and toxicity for combined of Dox XR can be overcome.