Combining etoposide and dexrazoxane synergizes with radiotherapy and improves survival in mice with central nervous system tumors

TY - JOUR

T1 - Combining etoposide and dexrazoxane synergizes with radiotherapy and improves survival in mice with central nervous system tumors

AU - Hofland, Kenneth Francis

AU - Thougaard, Annemette Vinding

AU - Dejligbjerg, Marielle

AU - Jensen, Lars H

AU - Kristjansen, Paul E G

AU - Lundegaard, Pia Rengtved

AU - Sehested, Maxwell

AU - Jensen, Peter Buhl

PY - 2005/9/15

Y1 - 2005/9/15

N2 - PURPOSE: The treatment of patients with brain metastases is presently ineffective, but cerebral chemoradiotherapy using radiosensitizing agents seems promising. Etoposide targets topoisomerase II, resulting in lethal DNA breaks; such lesions may increase the effect of irradiation, which also depends on DNA damage. Coadministration of the topoisomerase II catalytic inhibitor dexrazoxane in mice allows for more than 3-fold higher dosing of etoposide. We hypothesized that dexrazoxane combined with escalated etoposide doses might improve the efficacy of cerebral radiotherapy.EXPERIMENTAL DESIGN: Mice with cerebrally inoculated Ehrlich ascites tumor (EHR2) cells were treated with combinations of etoposide + dexrazoxane + cerebral radiotherapy. Similar chemotherapy and radiation combinations were investigated by clonogenic assays using EHR2 cells, and by DNA double-strand break assay through quantification of phosphorylated histone H2AX (gammaH2AX).RESULTS: Escalated etoposide dosing (90 mg/kg) combined with dexrazoxane (125 mg/kg) and cerebral radiotherapy (10 Gy x 1) increased the median survival by 60% (P = 0.001) without increased toxicity, suggesting that escalated etoposide levels may indeed represent a new strategy for improving radiotherapy. Interestingly, 125 mg/kg dexrazoxane combined with normal etoposide doses (34 mg/kg) also increased survival from radiotherapy, but only by 27% (P = 0.002). This indicates a direct dexrazoxane modulation of the combined effects of etoposide and radiation in brain tumors. Further, in vitro, concurrent dexrazoxane, etoposide, and irradiation significantly increased DNA double-strand breaks.CONCLUSION: Combining etoposide (high or normal doses) and dexrazoxane synergizes with cerebral radiotherapy and significantly improves survival in mice with central nervous system tumors. This regimen may thus improve radiation therapy of central nervous system tumors.

AB - PURPOSE: The treatment of patients with brain metastases is presently ineffective, but cerebral chemoradiotherapy using radiosensitizing agents seems promising. Etoposide targets topoisomerase II, resulting in lethal DNA breaks; such lesions may increase the effect of irradiation, which also depends on DNA damage. Coadministration of the topoisomerase II catalytic inhibitor dexrazoxane in mice allows for more than 3-fold higher dosing of etoposide. We hypothesized that dexrazoxane combined with escalated etoposide doses might improve the efficacy of cerebral radiotherapy.EXPERIMENTAL DESIGN: Mice with cerebrally inoculated Ehrlich ascites tumor (EHR2) cells were treated with combinations of etoposide + dexrazoxane + cerebral radiotherapy. Similar chemotherapy and radiation combinations were investigated by clonogenic assays using EHR2 cells, and by DNA double-strand break assay through quantification of phosphorylated histone H2AX (gammaH2AX).RESULTS: Escalated etoposide dosing (90 mg/kg) combined with dexrazoxane (125 mg/kg) and cerebral radiotherapy (10 Gy x 1) increased the median survival by 60% (P = 0.001) without increased toxicity, suggesting that escalated etoposide levels may indeed represent a new strategy for improving radiotherapy. Interestingly, 125 mg/kg dexrazoxane combined with normal etoposide doses (34 mg/kg) also increased survival from radiotherapy, but only by 27% (P = 0.002). This indicates a direct dexrazoxane modulation of the combined effects of etoposide and radiation in brain tumors. Further, in vitro, concurrent dexrazoxane, etoposide, and irradiation significantly increased DNA double-strand breaks.CONCLUSION: Combining etoposide (high or normal doses) and dexrazoxane synergizes with cerebral radiotherapy and significantly improves survival in mice with central nervous system tumors. This regimen may thus improve radiation therapy of central nervous system tumors.

KW - Animals

KW - Antineoplastic Combined Chemotherapy Protocols

KW - Blood-Brain Barrier

KW - Central Nervous System Neoplasms

KW - Combined Modality Therapy

KW - DNA Damage

KW - DNA, Neoplasm

KW - Dose-Response Relationship, Drug

KW - Dose-Response Relationship, Radiation

KW - Etoposide

KW - Female

KW - Mice

KW - Mice, Inbred Strains

KW - Neoplasms, Experimental

KW - Razoxane

KW - Survival Analysis

KW - Time Factors

KW - Treatment Outcome

KW - Tumor Cells, Cultured

U2 - 10.1158/1078-0432.CCR-05-0698

DO - 10.1158/1078-0432.CCR-05-0698

M3 - Journal article

C2 - 16166453

SN - 1078-0432

VL - 11

SP - 6722

EP - 6729

JO - Clinical Cancer Research

JF - Clinical Cancer Research

IS - 18

ER -