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


METHODS
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.


CONCLUSIONS
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.
Hofland
Kenneth Francis
KF
Laboratory of Experimental Medical Oncology, The Finsen Center, Copenhagen, Denmark. kfh@topotarget.com
Thougaard
Annemette Vinding
AV
Dejligbjerg
Marielle
M
Jensen
Lars H
LH
Kristjansen
Paul E G
PE
Rengtved
Pia
P
Sehested
Maxwell
M
Jensen
Peter Buhl
PB
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D016543:Central Nervous System Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D003131:Combined Modality Therapy; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D051379:Mice; D008815:Mice, Inbred Strains; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy; D011929:Razoxane / Q000008:administration & dosage; D016019:Survival Analysis; D013997:Time Factors; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
D004273:DNA, Neoplasm; D011929:Razoxane; D005047:Etoposide