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Blood, Vol. 109, Issue 1, 306-314, January 1, 2007
INNO-406, a novel BCR-ABL/Lyn dual tyrosine kinase inhibitor, suppresses the growth of Ph+ leukemia cells in the central nervous system, and cyclosporine A augments its in vivo activity
Blood Yokota et al.
109: 306
Supplemental materials for: Yokota et al, Vol 109, Issue 1, 306-314
Files in this Data Supplement:
- Table S1. Patients who developed CNS leukemia under imatinib treatment (PDF, 165 KB)
- Figure S1. In vitro–combined effects of INNO-406 and CsA or verapamil on P-gp–overexpressing cell line K562/D1-9 (PDF, 17.6 KB) -
To evaluate the combined effects of INNO-406 and CsA (A) and verapamil (B), the combination indexes (CIs) were calculated according to the method of Chou1 using CalcuSyn for Windows software (Biosoft, Ferguson, MO) as described elsewhere.2 This method provides quantitation of synergism (CI < 1) and antagonism (CI > 1) at different dose and effect levels. The fraction affected (Fa) at each dilution was calculated (ie, a Fa of 0.25 would correspond to 75% viable cells). CI was calculated under the assumption that the mechanisms of action of the drugs evaluated were not mutually exclusive.
- Figure S2. Mouse brain treated with INNO-406 and sequence of Abl kinase domain (PDF, 160 KB) -
(A) The brain of a mouse treated with 120 mg INNO-406/kg/day was massively infiltrated with GFP-positive leukemic cells just before the mouse’s death. (B) A 714-bp (base pair) region of ABL that codes for the ATP-binding site and the kinase activation loop was PCR-amplified using 3 primer pairs and (C) directly sequenced in 3 complementary DNAs taken from Ba/F3/wt bcr-ablGFP and leukemic cells in the brain of INNO-406–treated mice.
- Figure S3. In vivo effect of CsA and INNO-406 alone and in combination on survival in engrafted mice (PDF, 14.1 KB) -
The lines represent the survival rate of 4 treatment groups. Administration of INNO-406, CsA, or both was initiated on day 1. (i) Untreated mice, black; (ii) mice treated with 60 mg INNO-406/kg per day for 10 days, pink; (iii) mice treated with 50 mg CsA/kg per day for 10 days, blue; (iv) mice treated with 60 mg INNO-406/kg per day and 50 mg CsA/kg per day for 10 days, red. Each group contained 7 mice.
- Figure S4. Growth inhibitory effects of 2-hour exposure of INNO-406 (PDF, 19.3 KB) -
Ba/F3/wt bcr-ablGFP cells (5 × 105 cells/mL) were exposed to saline or 0.06, 0.12, and 0.24 µM INNO-406 for 2 hours and then washed 3 times. Then cells were resuspended at 5 × 105 cells/mL and incubated for 48 hours. The numbers of living cells were determined at 24 and 48 hours by trypan blue dye exclusion.
REFERENCES
1. Chou TC. The median effect principal and the combination index for quantitation of synergism and antagonism. In: Chou TC, Rideout DC, eds. Synergism and Antagonism in Chemotherapy. San Diego, CA: Academic Press, 1977:61-102.
2. Kimura S, Kuroda J, Segawa H, et al. Antiproliferative efficacy of the third generation bisphosphate zoledronic acid combined with other anticancer drugs in leukemic cell lines. Int J Hematol. 2004;79:37-43.
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