Initial testing (stage 1) of temozolomide by the pediatric preclinical testing program1. Issue 5 (17th January 2013)

• Record Type: Journal Article
• Authors: Keir, Stephen T.; Maris, John M.; Reynolds, C. Patrick; Kang, Min H.; Kolb, E. Anders; Gorlick, Richard; Lock, Richard; Carol, Hernan; Morton, Christopher L.; Wu, Jianrong; Kurmasheva, Raushan T.; Houghton, Peter J.; Smith, Malcolm A.
• Is Part Of: Pediatric blood & cancer. Volume 60:Issue 5(2013:May)
• Page Start: 783
• Page End: 790
• Publication Date: 2013-01-17
• Subjects: Tumors in children -- Periodicals; Blood -- Diseases -- Periodicals; Cancer in children -- Periodicals; 618.92
• DOI: 10.1002/pbc.24368
• Languages: English
• ISSNs: 1545-5009

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <sec id="abs1-1" sec-type="section"> <title>Background</title> <p>The DNA methylating agent temozolomide was developed primarily for treatment of glioblastoma. However, preclinical data have suggested a broader application for treatment of childhood cancer. Temozolomide was tested against the PPTP solid tumor and ALL models.</p> </sec> <sec id="abs1-2" sec-type="section"> <title>Procedures</title> <p>Temozolomide was tested against the PPTP <italic>in vitro</italic> panel at concentrations ranging from 0.1 to 1, 000 µM and was tested against the PPTP <italic>in vivo</italic> panels at doses from 22 to 100 mg/kg administered orally daily for 5 days, repeated at day 21.</p> </sec> <sec id="abs1-3" sec-type="section"> <title>Results</title> <p> <italic>In vitro</italic> temozolomide showed cytotoxicity with a median relative IC<sub>50</sub> (rIC<sub>50</sub>) value of 380 µM against the PPTP cell lines (range 1 to > 1, 000 µM). The three lines with rIC<sub>50</sub> values lesser than 10 µM had low MGMT expression compared to the remaining cell lines. <italic>In vivo</italic> temozolomide demonstrated significant toxicity at 100 mg/kg, but induced tumor regressions in 15 of 23 evaluable solid tumor models (13 maintained CR [MCR], 2 CR) and 5 of 8 ALL models (3 MCR, 2 CR). There was a steep dose response curve, with lower activity at 66 mg/kg temozolomide and with tumor regressions at 22 and 44 mg/kg restricted to models with low MGMT expression.</p> </sec> <sec id="abs1-4" sec-type="section"> <title>Conclusions</title> <p>Temozolomide demonstrated high level antitumor activity against both solid tumor and leukemia models, but also elicited significant toxicity at the highest dose level. Lowering the dose of TMZ to more closely match clinical exposures markedly reduced the antitumor activity for many xenograft lines with responsiveness at lower doses closely related to low MGMT expression. Pediatr Blood Cancer 2013; 60: 783–790. © 2013 Wiley Periodicals, Inc.</p> </sec> </abstract>