Article Figures & Data
Figures
- Fig. 1.
Responses of Rh28 rhabdomyosarcoma xenografts in SCID mice to Irofulven treatment. Irofulven was administered i.v. daily for 5 days. Courses of therapy were repeated every 21 days for a total of three cycles. A, control; B, 3.0 mg/kg; C, 2.0 mg/kg; and D, 1.32 mg/kg. Tumor volumes were determined every 7 days. Each curve represents growth of an individual tumor. E, relative tumor volumes for tumors in control (○), B, (•); C, (□); and D, (▪). F, survival.
- Fig. 2.
Responses of SJ-BT40 ATRT xenografts in SCID mice to Irofulven treatment. Irofulven was administered i.v. daily for 5 days. Courses of therapy were repeated every 21 days for a total of three cycles. A, control; B, 7.0 mg/kg; C, 4.6 mg/kg; D, 3.0 mg/kg; E, 2.0 mg/kg; and F, 1.32 mg/kg. Tumor volumes were determined every 7 days. Each curve represents growth of an individual tumor.
- Fig. 3.
Irofulven plasma concentration versus time plot after i.v. Irofulven for tumor-bearing animals. The line represents the best-fit line from the pharmacokinetic analysis.
Tables
- Table 1
Histology of brain tumor xenografts
Xenograft designation Histology SJ-BT12 ATRT SJ-BT16 ATRT SJ-BT27 Primitive neuroectodermal tumor (PNET) SJ-BT29 ATRT SJ-BT30 Juvenile pilocytic astrocytoma SJ-BT33 Subependymal giant cell astrocytoma SJ-BT34 ATRT SJ-BT37 ATRT SJ-BT40 ATRT - Table 2
Antitumor activity of Irofulven against pediatric tumor xenografts
Tumor Dose level (mg/kg) 7.0 4.6 3.0 2.0 1.3a DAOY ++++++ ++++++ ++++++ +++++ ++ D283 ++++++ ++++++ ++++++ +++ +a SJ-BT12 ND ++++ +/−a −a −a SJ-BT16 +++ ++++ +++ ++ +a SJ-BT27 ND ++++++ ++++++ +++ + SJ-BT29 ++++++ +++ +++a ND ND SJ-BT33 −a −a −a −a −a SJ-BT34 ++++++ ++++++ ++++++ ND ND SJ-BT36 ++++++ ++++++ ++++ +++ +++a SJ-BT37 ++++++ +++++ +++ +a −a SJ-BT40 ++++ ++++ ++a +a −a SJ-GBM2 ++++++ ++++++ +a ND ND NB-1771 ND ND + −a −a NB-1382 ++++ ++++ +++a ND ND NB-1643 ++++++ ++++++ ++++ ND ND NB-1691 +++++ +++ ++ +a ND Rh18 ++++++ ++++ ++++ +++ ++ Rh28 ++++++ ++++++ ++++++ +++++ +++ Rh30 ND ND ND ++++++ ++++++ Rh36 ++++ +++ ++ +a −a CR+PR/total 14/16 14/18 8/19 3/15 1/14 -
a Growth inhibition not significant (P > 0.05). All other results were significantly different from controls (P < 0.05).
-
b Response criteria: ++++++, CR maintained at week 12 (no regrowth by week 12); +++++, CR with regrowth by week 12; ++++, PR (≥50% regression); +++, growth stasis; ++, growth inhibition equals 2 tumor-volume doubling times; +, growth inhibition equals 1 tumor-volume doubling time; −, no growth inhibition; and ND, not determined.
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- Table 3
Minimum effective Irofulven dose associated with objective regressions of xenografts after i.v. administration
Dose (mg/kg) Tumor lines MGI AUC (ng/ml∗h) 1.3 Rh30 214 2.0 Rh28, DAOY 329 3.0 D283, SJ-BT27, SJ-BT34a, SJ-BT36, NB1643 494 4.6 SJ-BT12, SJ-BT16, SJ-BT37, SJ-BT40, SJ-GBM2, NB-1382, Rh18 757 7.0 SJ-BT29, NB-1691, Rh36 1152 -
a Lowest dosage level evaluated.
-
- Table 4
Irofulven disposition is linear in nontumor-bearing mice
Dosage (mg/kg) Cmax (ng/ml) AUC0→∞ (ng/ml∗h) t1/2β (min) 3.0 1200 310 34.5 4.6 6500 970 45.5 7.0 9064 1152 54.5 - Table 5
Summary of Irofulven pharmacokinetic parameter estimates after i.v. administration
Pharmacokinetic parameter Nontumor SJ-BT29 SJ-BT33 ke (h−1) 7.5 ± 1.0 6.5 5.2 Vc (liter/m2) 0.00238 ± 0.001 0.00315 0.00377 t1/2α (min) 5.4 ± 0.8 6.0 7.4 t1/2β (min) 54.5 ± 12.5 105.6 82.8 Cl (liter/h/m2) 0.0166 ± 0.0042 0.0195 0.0194 Vdss (liter/m2) 0.0037 ± 0.0017 0.0079 0.0057 Cmax (ng/ml) 9064 ± 2788 7852 5675 AUC0→∞ (ng/ml∗h) 1152 ± 57 1011 1060
Volume 8, Issue 9
