title: Patupilone (epothilone B, EPO906) and imatinib (STI571, Glivec) in combination display enhanced antitumour activity in vivo against experimental rat C6 glioma.
abstract: OBJECTIVE
  The microtubule-stabilizing agent patupilone (epothilone B, EPO906) and the tyrosine kinase inhibitor imatinib (STI571, Glivec) which primarily inhibits Bcr-Abl, PDGF and c-Kit tyrosine kinase receptors, were combined in vivo to determine if any interaction would occur with respect to antitumour effect and tolerability using rat C6 glioma xenografted into nude mice.
  
  
  METHODS
  Patupilone and imatinib were administered alone or in combination at suboptimal doses. Imatinib treatment (orally once daily) was initiated 4 days after s.c. injection of rat C6 glioma cells into athymic nude mice and patupilone administration (i.v. once per week) was started 3 or 4 days after imatinib treatment.
  
  
  RESULTS
  As a single agent, imatinib was inactive in the regimens selected (100 mg/kg: T/C 86% and 116%; 200 mg/kg: T/C 68% and 84%; two independent experiments), but well tolerated (gain in body weight and no mortalities). Patupilone weekly monotherapy demonstrated dose-dependent antitumour effects (1 mg/kg: T/C 67% and 70%; 2 mg/kg: T/C 32% and 63%; 4 mg/kg: T/C 3% and 46%). As expected, dose-dependent body weight losses occurred (final body weight changes at 1 mg/kg were -7% and -3%; at 2 mg/kg were -23% and -13%; and at 4 mg/kg were -33% and -15%). Combining 2 mg/kg patupilone and 200 mg/kg per day imatinib in one experiment produced a non-statistically significant trend for an improved antitumour effect over patupilone alone (combination, T/C 9%), while in the second experiment, enhancement was seen with the combination and reached statistical significance versus patupilone alone (combination, T/C 22%; P=0.008). Reduction of the imatinib dose to 100 mg/kg per day resulted in no enhancement of antitumour activity in combination with 2 mg/kg patupilone. Reduction of the patupilone dose to 1 mg/kg resulted in a reduced antitumour effect, and only a trend for synergy with either imatinib dose (combination, T/C 46% and 40%). Pooling the data from the two experiments confirmed a significant synergy for the combination of 2 mg/kg patupilone and 200 mg/kg per day imatinib (P=0.032), and a trend for synergy at the 1 mg/kg patupilone dose. Reduction in the imatinib dose to 100 mg/kg per day resulted only in additivity with either dose of patupilone. Body weight losses were dominated by the effect of patupilone, since no greater body weight loss was observed in the combination groups.
  
  
  CONCLUSIONS
  Combining patupilone with high-dose imatinib produced an increased antitumour effect without affecting the tolerability of treatment in a relatively chemoresistant rat C6 glioma model. Such results indicate that further evaluation is warranted, in particular to elucidate possible mechanisms of combined action.
authors.affiliation: Oncology Research, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: T
authors.initials: T
authors.lastname: O'Reilly
authors.affiliation: Oncology Research, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Wartmann
authors.affiliation: Oncology Research, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: S-M
authors.initials: SM
authors.lastname: Maira
authors.affiliation: Oncology Research, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Hattenberger
authors.affiliation: Oncology Research, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: J
authors.initials: J
authors.lastname: Vaxelaire
authors.affiliation: Oncology Research, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Muller
authors.affiliation: Oncology Research, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Ferretti
authors.affiliation: Oncology Research, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: E
authors.initials: E
authors.lastname: Buchdunger
authors.affiliation: Oncology Research, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: K-H
authors.initials: KH
authors.lastname: Altmann
authors.affiliation: Oncology Research, Novartis Institutes for BioMedical Research, Basel, Switzerland. paul_mj.mcsheehy@pharma.novartis.com.
authors.forename: P M J
authors.initials: PMJ
authors.lastname: McSheehy
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001549:Benzamides; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D034261:Epothilones / Q000008:administration & dosage*; D005910:Glioma / Q000188:drug therapy*; D000068877:Imatinib Mesylate; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010879:Piperazines / Q000008:administration & dosage*; D011743:Pyrimidines / Q000008:administration & dosage*; D051381:Rats
chemical_list: D001549:Benzamides; D034261:Epothilones; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; C093788:epothilone B