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

Williams JR, Zhang Y, Zhou H, Gridley DS, Koch CJ, Dicello JF, Slater JM, Little JB - Radiat Oncol (2010)

Bottom Line: Each group associates with a specific genotype.We analyze these data to derive coefficients that describe both in vitro and in vivo responses.Both coefficients are dependent on tumor cell genotype and fraction-size.

View Article: PubMed Central - HTML - PubMed

Affiliation: Radiation Research Laboratories, Department of Radiation Medicine, Loma Linda University Medical Center, Loma Linda, CA, USA. jrwilliams_france@yahoo.com

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 x 2 Gy; 2 x 5 Gy, 1 x 7.5 Gy and 1 x 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.

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In vitro cellular radiosensitivity of eight cell lines used in figure 1 presented within a data matrix representing the spectrum of tumor cell radiosensitivity. Data are expressed as the ratio of coefficients that describe the slope of clonogenic inactivation at lower doses α(SF2) and ω*, the rate of additional clonogenic inactivation at higher doses.
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Figure 2: In vitro cellular radiosensitivity of eight cell lines used in figure 1 presented within a data matrix representing the spectrum of tumor cell radiosensitivity. Data are expressed as the ratio of coefficients that describe the slope of clonogenic inactivation at lower doses α(SF2) and ω*, the rate of additional clonogenic inactivation at higher doses.

Mentions: We show these data in figure 2 for survival data in figure 1 placing radiosensitivity of these ten cell lines in a structure of coefficients that describe their radiosensitivity within a framework of radiosensitivity for 39 cell lines. Radiosensitivity of each cell line is expressed as defined by the ratio of cell killing at circa 2 Gy, α (SF2) to additional cell killing at doses higher than 4.0 Gy, ω*. This figure shows the relative cellular radiosensitivity of the eight cells used in the experiments present as four diagonal lines, each line associated with a specific genotype.


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

Williams JR, Zhang Y, Zhou H, Gridley DS, Koch CJ, Dicello JF, Slater JM, Little JB - Radiat Oncol (2010)

In vitro cellular radiosensitivity of eight cell lines used in figure 1 presented within a data matrix representing the spectrum of tumor cell radiosensitivity. Data are expressed as the ratio of coefficients that describe the slope of clonogenic inactivation at lower doses α(SF2) and ω*, the rate of additional clonogenic inactivation at higher doses.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2927609&req=5

Figure 2: In vitro cellular radiosensitivity of eight cell lines used in figure 1 presented within a data matrix representing the spectrum of tumor cell radiosensitivity. Data are expressed as the ratio of coefficients that describe the slope of clonogenic inactivation at lower doses α(SF2) and ω*, the rate of additional clonogenic inactivation at higher doses.
Mentions: We show these data in figure 2 for survival data in figure 1 placing radiosensitivity of these ten cell lines in a structure of coefficients that describe their radiosensitivity within a framework of radiosensitivity for 39 cell lines. Radiosensitivity of each cell line is expressed as defined by the ratio of cell killing at circa 2 Gy, α (SF2) to additional cell killing at doses higher than 4.0 Gy, ω*. This figure shows the relative cellular radiosensitivity of the eight cells used in the experiments present as four diagonal lines, each line associated with a specific genotype.

Bottom Line: Each group associates with a specific genotype.We analyze these data to derive coefficients that describe both in vitro and in vivo responses.Both coefficients are dependent on tumor cell genotype and fraction-size.

View Article: PubMed Central - HTML - PubMed

Affiliation: Radiation Research Laboratories, Department of Radiation Medicine, Loma Linda University Medical Center, Loma Linda, CA, USA. jrwilliams_france@yahoo.com

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 x 2 Gy; 2 x 5 Gy, 1 x 7.5 Gy and 1 x 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.

Show MeSH
Related in: MedlinePlus