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• W2895458839 abstract "1343 Tumor re-growth is clinically observed at the time of arrest of anti-EGFR therapies. The aim of the present study was to compare, for a similar dose exposure to anti-EGFR therapies, a constant schedule with a tapered schedule (i.e. progressive dose reduction). Both the mAb cetuximab (i.p. administration) and the TKI gefitinib (p.o. administration) were tested. A human head and neck cancer cell line exhibiting high EGFR levels (CAL33) was subcutaneously implanted in the flank of nude mice (15 mice per condition). Constant schedule consisted in 7 days cetuximab (1.14 mg/kg/d) or gefitinib (68.4 mg/kg/d) administration. Tapered schedule consisted in 7 days cetuximab (1 mg/kg/d) or gefitinib (60 mg/kg/d) followed by 7 days administration at decreased doses (divided by 2 every day). Equal total doses were given for both schedules. Five mice in each treatment group were sacrificed at the 3 following times (day 0 = start of treatment): day 7, day 14, and at the end of observation when mean tumor volume in the group reached 2000 mm 3 . Tumor volume and time to reach a mean tumor volume of 1000 mm 3 (TRV) were measured. At each time, tumor EGFR expression along with the EGFR-signalling proteins p-Erk, p-Akt, apoptosis-related factors Bax/Bcl2 and % cleaved Parp (Western blot analyses) were analyzed.
 Of note, tumor growth with gefitinib at the constant schedule did not differ from controls, whereas gefitinib at the tapered schedule significantly slowed down tumor re-growth (difference in TRV between schedules = 7 days). Cetuximab treatment was effective with both schedules, with a stronger growth inhibition and lasting effect with the tapered schedule as compared to the constant schedule (difference in TRV between schedules = 10 days). For both drugs, these effects were paralleled by a significant down-regulation of EGFR expression relative to controls (on day 7 and day 14). The EGFR down-regulation observed with gefitinib lasted longer with the tapered schedule than with the constant schedule, whereas that observed with cetuximab was similar with both schedules. Significant effects on EGFR signalling proteins were only observed with cetuximab at the constant schedule, with decreases in p-Akt and p-Erk expression (both at the end of observation) and parallel increases in the apoptosis markers Bax/Bcl2 (on day 7 and day 14) and cleaved Parp (at the end of observation).
 The present data clearly show that for both anti-EGFR monoclonal antibody and TKI, a tapered schedule more efficiently slowed down the tumor re-growth as compared to a constant schedule given at the same total drug exposure. This new drug schedule, unexplored so far in the clinical setting, could be of interest in the management of anti-EGFR-based therapies, in particular for TKIs." @default.
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• W2895458839 date "2008-05-01" @default.
• W2895458839 modified "2023-10-18" @default.
• W2895458839 title "Tapered versus constant drug exposure to anti-EGFR monoclonal antibody (mAb) and tyrosine kinase inhibitor (TKI)." @default.
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