481 Cytokinesis Blocked Micronucleus (Cbmn) Assay Is Predictive of Gastrointestinal (GI) Sequeale 2 Years Following Radiation Therapy (RT) for Prostate Carcinoma (CAP) Whilst Micronutrients Reduce Their Severity

Abstract

RT for CaP is associated with GI sequelae including anorectal dysfunction up to 5 years after RT(1). Patients receive the same radiation dose despite variations in normal tissue tolerance(2). The CBMN assay quantifies spontaneous and radiation-induced DNA damage in peripheral blood lymphocytes(3) and has been correlated with GI sequelae after RT for CaP(2,4). The molecular basis of radiation sensitivity and role of dietary micronutrients on GI sequelae is unknown. This prospective study aims to develop biomarkers predictive for GI sequelae after RT for CaP, identifying modifying dietary and genetic factors.Methods:Before RT, venous blood of 21 patients 69(55-79)yrs with CaP, was assayed for (i)CBMN, (ii)plasma homocysteine, B12, folate, Zn, Se, lutein, retinol, α-tocopherol, lycopene and α-carotene and (iii)genotyping. LENT-SOMA GI symptoms(1), anorectal manometry and endoanal ultrasound were evaluated before RT, 1mth, 1 and 2yrs after RT(3). Data analyzed by ANOVA. Relationships among the anorectal function parameters and rectal volumes, CBMN and micronutrient data were examined by linear regression. Results:GI symptoms increased after RT and persisted at 2yrs. This was associated with reductions in (i)basal pressures, (ii)pressures in response to increased intra-abdominal pressure, (iii)rectal compliance, (iv)threshold volumes and (v)internal anal sphincter thickness. Spontaneous CBMN data were directly related to (a) 1 yr total GI symptom scores (r=0.52, p<0.05) and inversely related to squeeze pressures at 1 (r=-0.54, p<0.05) and 2 (r=-0.47, p<0.05) yrs. 1 mth desire to defecate volumes were also inversely related to radiation-induced (3Gy ex-vivo) CBMN index (r=-0.56, p<0.05). Plasma lycopene(r=-0.46, p<0.05) and α-carotene(r=-0.48, p<0.05) were inversely related to 1 yr diarrheal scores. Plasma α-carotene was also directly related to 1 yr threshold volumes (r=0.60, p<0.01). There were direct relationships between (a) plasma homocysteine and 1 yr diarrheal scores (r=0.62, p<0.01), (b) plasma zn and 1 yr basal pressures (r=0.45, p<0.05), (c) plasma retinol and 1 yr threshold volumes (r=0.59, p<0.01). Rectal bleeding scores at 1 mth were directly related to rectal volumes (r=0.48, p<0.05). Conclusion:The CBMN assay predicts GI sequelae 2 yrs after RT for CaP. Diets that include higher intake of foods rich in lycopene, α-carotene, zinc and retinol and which produce a lower homocysteine concentration in plasma, are likely to reduce the late adverse effects of RT for CaP. (1)Yeoh et al Am J Gastroenterol 2004, 2:361-369,(2)Lee et al Int J Radiat Oncol Biol Phys 2003,57:222-229,(3)Fenech, Mut Res 2000,455:81-95,(4)Yeoh et al,Gastroenterol 2007,132:A590