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Open Access Research

Tumor response to radiotherapy is dependent on genotype-associated mechanisms in vitro and in vivo

Jerry R Williams1*, Yonggang Zhang2, Haoming Zhou2, Daila S Gridley1, Cameron J Koch3, John F Dicello1, James M Slater1 and John B Little4

Author Affiliations

1 Radiation Research Laboratories, Department of Radiation Medicine, Loma Linda University Medical Center, Loma Linda CA, USA

2 Laboratory of Radiobiology, Johns Hopkins School of Medicine, Baltimore, MD, USA

3 Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA, USA

4 Center for Radiation Sciences and Environmental Health, Harvard School of Public Health, Boston, MA, USA

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Radiation Oncology 2010, 5:71  doi:10.1186/1748-717X-5-71

Published: 12 August 2010

Abstract

Background

We have previously shown that in vitro radiosensitivity of human tumor cells segregate non-randomly into a limited number of groups. Each group associates with a specific genotype. However we have also shown that abrogation of a single gene (p21) in a human tumor cell unexpectedly sensitized xenograft tumors comprised of these cells to radiotherapy while not affecting in vitro cellular radiosensitivity. Therefore in vitro assays alone cannot predict tumor response to radiotherapy.

In the current work, we measure in vitro radiosensitivity and in vivo response of their xenograft tumors in a series of human tumor lines that represent the range of radiosensitivity observed in human tumor cells. We also measure response of their xenograft tumors to different radiotherapy protocols. We reduce these data into a simple analytical structure that defines the relationship between tumor response and total dose based on two coefficients that are specific to tumor cell genotype, fraction size and total dose.

Methods

We assayed in vitro survival patterns in eight tumor cell lines that vary in cellular radiosensitivity and genotype. We also measured response of their xenograft tumors to four radiotherapy protocols: 8 × 2 Gy; 2 × 5Gy, 1 × 7.5 Gy and 1 × 15 Gy. We analyze these data to derive coefficients that describe both in vitro and in vivo responses.

Results

Response of xenografts comprised of human tumor cells to different radiotherapy protocols can be reduced to only two coefficients that represent 1) total cells killed as measured in vitro 2) additional response in vivo not predicted by cell killing. These coefficients segregate with specific genotypes including those most frequently observed in human tumors in the clinic. Coefficients that describe in vitro and in vivo mechanisms can predict tumor response to any radiation protocol based on tumor cell genotype, fraction-size and total dose.

Conclusions

We establish an analytical structure that predicts tumor response to radiotherapy based on coefficients that represent in vitro and in vivo responses. Both coefficients are dependent on tumor cell genotype and fraction-size. We identify a novel previously unreported mechanism that sensitizes tumors in vivo; this sensitization varies with tumor cell genotype and fraction size.