Biologically-Based Biologically-Based Estimates of Radiation-Estimates of Radiation-

Induced CML RiskInduced CML Risk

Tom RadivoyevitchAssistant ProfessorEpidemiology and BiostatisticsCase Western Reserve University

Email: txr24@case.eduWebsite: http://epbi-radivot.cwru.edu/

Linear Risk Model

itkc

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i mmO )log( we maximized the log-likelihood

Using the BCR-ABL to CMLwaiting time density

and the linear model

Model of Radiation-Model of Radiation-Induced CML RiskInduced CML Risk

)(222

21 ])([ niknikikitniDDD

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A linear-quadratic-exponential model of CML risk isA linear-quadratic-exponential model of CML risk is

DDii and and DDni ni are the gamma and neutron doses in grayare the gamma and neutron doses in grayNN is the number of CML target cells per adult is the number of CML target cells per adult PP((ba|Tba|T)) is the probability of is the probability of BCRBCR--ABLABL given a translocation given a translocation

This is a one-stage model of carcinogenesis.This is a one-stage model of carcinogenesis.

wherewhere

BCR-to-ABL 2D distances in lymphocytes

Kozubek et al. (1999) Chromosoma 108: 426-435

Theory of Dual Radiation Theory of Dual Radiation ActionAction

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

2

02

2 )()(4

)(2)|( DDdrrgrS

r

rtDYTTDbaP bababa

DABLBCR

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Estimation of g(r)

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4

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1drerSGp rr

d

G=35 DSB/Gy per cell

6.25 kev/um3 = 1 Gy

R = 3.7 um r0 = 0.24 m, p0 = 0.06

d in [.01, .025], dx in [.04, .05], d in [.05, .06]

Model of Radiation-Model of Radiation-Induced CML RiskInduced CML Risk

)(222

21 ])([ niknikikitniDDD

itkc

iniiikac

i ePetDDDem

ittkcii ettwTbaPN 22)()|(

A linear-quadratic-exponential model of CML risk isA linear-quadratic-exponential model of CML risk is

DDii and and DDni ni are the gamma and neutron doses in grayare the gamma and neutron doses in grayNN is the number of CML target cells per adult is the number of CML target cells per adult PP((ba|Tba|T)) is the probability of is the probability of BCRBCR--ABLABL given a translocation given a translocation

This is a one-stage model of carcinogenesis.This is a one-stage model of carcinogenesis.

wherewhere

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.

DiscussionDiscussion

CML low incidence=> CML risk estimates will CML low incidence=> CML risk estimates will not change protection policies => low priority not change protection policies => low priority for fundingfor funding

Focus on well understood systems to connect Focus on well understood systems to connect basic science to epi-data. Works better in basic science to epi-data. Works better in cancer therapy, e.g. gleevec.cancer therapy, e.g. gleevec.

Specialize modelers to become experts in Specialize modelers to become experts in biological literatures: Tyson career modelbiological literatures: Tyson career model

dNTP Supply System

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.

UDP

CDP

GDP

ADP

dTTP

dCTP

dGTP

dATP

dT

dC

dG

dA

DNA

dUMP

dU

TS

DCTD

dCK

DN

A p

olym

eras

eTK1

cytosol

mitochondria

dT

dC

dG

dA

TK

2dG

K

dTMP

dCMP

dGMP

dAMP

dTTP

dCTP

dGTP

dATP

5NT

NT2

cytosol

nucleus

dUDP

dUTPdUTPase

dN

dN

dCK

flux activation inhibition

ATPordATP

RN

R

dCK

Metabolism of Metabolism of dNTPs + AnalogsdNTPs + Analogs

Metabolism of Metabolism of DNA + Drug-DNADNA + Drug-DNA

Damage DrivenDamage Drivenor or

S-phase DrivenS-phase Driven

dNTP demand dNTP demand is eitheris either

Focus on cancers Focus on cancers caused by DNA repair caused by DNA repair system failuressystem failures

DNA repairDNA repair

SalvageSalvage

De novoDe novo

Focus on Focus on nucleoside nucleoside analogsanalogs

CASE ICBP CASE ICBP Problem StatementProblem Statement

For Example:For Example:

Carcinogenesis and Carcinogenesis and TherapyTherapy

Childhood leukemia treatments as carcinogen Childhood leukemia treatments as carcinogen exposures: secondary AMLs account for 50% of exposures: secondary AMLs account for 50% of treatment failures; whole lifetimes to see solids treatment failures; whole lifetimes to see solids arise.arise.

System models (e.g. dNTP supply) can be applied System models (e.g. dNTP supply) can be applied to carcinogenesis and therapyto carcinogenesis and therapy

Focus on well understood cancers first. Cannot cure Focus on well understood cancers first. Cannot cure everyone - cannot predict risks of all compounds everyone - cannot predict risks of all compounds for all endpoints. for all endpoints.