Biologically-Based Estimates of Radiation-Induced CML Risk

1. Biologically-Based Estimates of Radiation-Induced CML Risk Tom Radivoyevitch Assistant Professor Epidemiology and Biostatistics Case Western Reserve University Email: txr24@case.edu Website: http://epbi-radivot.cwru.edu/

3. Linear Risk Model Using the BCR-ABL to CML waiting time density and the linear model we maximized the log-likelihood

4. Model of Radiation-Induced CML Risk A linear-quadratic-exponential model of CML risk is where Di and Dni are the gamma and neutron doses in gray N is the number of CML target cells per adult P(ba|T)is the probability of BCR-ABL given a translocation This is a one-stage model of carcinogenesis.

5. BCR-to-ABL 2D distances in lymphocytes Kozubek et al. (1999) Chromosoma 108: 426-435

6. Theory of Dual Radiation Action • P(ba|D)= probability of a BCR-ABL translocation per G0/G1 cell given a dose D • tD(r)dr = expected energy at r given an ionization event at the origin • = intra-track component + inter-track component • Sba(r) = the BCR-to-ABL distance probability density • g(r) = probability that two DSBs misrejoin if they are created r units apart • Y = 0.0058 DSBs per Mb per Gy;  = mass density • TBCR = 5.8 kbp; TABL = 300 kbp

7. Estimation of g(r) din [.01, .025], dx in [.04, .05], d in [.05, .06] G=35 DSB/Gy per cell 6.25 kev/um3 = 1 Gy R = 3.7 um r0 = 0.24 m, p0 = 0.06

9. Model of Radiation-Induced CML Risk A linear-quadratic-exponential model of CML risk is where Di and Dni are the gamma and neutron doses in gray N is the number of CML target cells per adult P(ba|T)is the probability of BCR-ABL given a translocation This is a one-stage model of carcinogenesis.

11. Figure 3: Hypersensitivity ratios in the literature (left panel) and the log-survival dose response for T98G human glioma cells (right panel). Figures from Joiner, M.C., Marples, B., Lambin, P., Short, S.C. and Turesson, I., Low-dose hypersensitivity: current status and possible mechanisms. Int J Radiat Oncol Biol Phys (2001) 49: 379-389.

12. Discussion • CML low incidence=> CML risk estimates will not change protection policies => low priority for funding • Focus on well understood systems to connect basic science to epi-data. Works better in cancer therapy, e.g. gleevec. • Specialize modelers to become experts in biological literatures: Tyson career model

13. DNA polymerase TK1 dNTP Supply System flux activation inhibition nucleus ADP dATP dA GDP dGTP DNA dCK dG dCTP CDP dCK dCK RNR ATP or dATP mitochondria dC dTTP UDP DCTD cytosol cytosol 5NT TS dA dAMP dATP dUMP dUDP dGK dT dG dGMP dGTP dU dUTP dUTPase dC dN dCMP dCTP TK2 dT dTMP dTTP NT2 dN Figure 1.dNTP supply. Many anticancer agents act on or through this system to kill cells. The most central enzyme of this system is RNR.

14. CASE ICBP Problem Statement Damage Driven or S-phase Driven Focus on nucleoside analogs dNTP demand is either Salvage Metabolism of dNTPs + Analogs Metabolism of DNA + Drug-DNA De novo Focus on cancers caused by DNA repair system failures DNA repair For Example:

15. Carcinogenesis and Therapy • Childhood leukemia treatments as carcinogen exposures: secondary AMLs account for 50% of treatment failures; whole lifetimes to see solids arise. • System models (e.g. dNTP supply) can be applied to carcinogenesis and therapy • Focus on well understood cancers first. Cannot cure everyone - cannot predict risks of all compounds for all endpoints.