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Combination treatment for myeloproliferative neoplasms using JAK and pan-class I PI3K inhibitors.

Choong ML, Pecquet C, Pendharkar V, Diaconu CC, Yong JW, Tai SJ, Wang SF, Defour JP, Sangthongpitag K, Villeval JL, Vainchenker W, Constantinescu SN, Lee MA - J. Cell. Mol. Med. (2013)

Bottom Line: Synergy was not observed in Bcr-Abl transformed cells.The best JAK2/JAK1 and PI3K inhibitor combination pair (ruxolitinib and GDC0941) reduces spleen weight in nude mice inoculated with Ba/F3 cells expressing TpoR and JAK2 V617F.Our data support the use of a combination of JAK2 and pan-class I PI3K inhibitors in the treatment of MPNs.

View Article: PubMed Central - PubMed

Affiliation: Experimental Therapeutics Centre, Agency for Science Technology and Research, Singapore.

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Related in: MedlinePlus

Effect of JAK and PI3K inhibitions on survival (A) and spleen weight (B) in the JAK2 mutation-driven leukaemia mouse model. Ba/F3 TpoR JAK2 V617F cells (1 × 107) were intravenously inoculated into 8- to 10-week-old female nude mice. After 3 days, mice were treated with either vehicle, GDC0941 alone at 50 mg/kg body weight, ruxolitinib alone at 50 mg/kg body weight, or a combination of both compounds for 12 days. Combination treatment increased survival by 2 days compared with single compound treatment. Combination treatment also reduced spleen weight significantly compared with vehicle-treated mice, or mice treated with GDC0941 alone, or ruxolitinib alone (*P < 0.001 for each comparison). qd: every day, bid: twice a day.
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fig05: Effect of JAK and PI3K inhibitions on survival (A) and spleen weight (B) in the JAK2 mutation-driven leukaemia mouse model. Ba/F3 TpoR JAK2 V617F cells (1 × 107) were intravenously inoculated into 8- to 10-week-old female nude mice. After 3 days, mice were treated with either vehicle, GDC0941 alone at 50 mg/kg body weight, ruxolitinib alone at 50 mg/kg body weight, or a combination of both compounds for 12 days. Combination treatment increased survival by 2 days compared with single compound treatment. Combination treatment also reduced spleen weight significantly compared with vehicle-treated mice, or mice treated with GDC0941 alone, or ruxolitinib alone (*P < 0.001 for each comparison). qd: every day, bid: twice a day.

Mentions: Female BALB/c nude mice injected with Ba/F3 TpoR JAK2 V617F cells were studied for overall survival and enlargement of spleen (Fig. 5). Tissue samples were collected from mice killed on day 8 and day 14. Spleen weight increased after 8 days of cell implantation, while increase of liver weight was observed by day 14 (Fig. S5A). A progressive increase of Ba/F3 TpoR JAK2 V617F cells in the systemic blood circulation and spleen was observed from day 8 to day 14 (Fig. S5B). An increase of Ba/F3 TpoR JAK2 V617F cells in the bone marrow was observed on day 8 (results not shown). Platelet and red blood cell numbers decreased when compared with the control groups, most likely because of replacement by proliferating Ba/F3 transformed cells (Fig. S5C).


Combination treatment for myeloproliferative neoplasms using JAK and pan-class I PI3K inhibitors.

Choong ML, Pecquet C, Pendharkar V, Diaconu CC, Yong JW, Tai SJ, Wang SF, Defour JP, Sangthongpitag K, Villeval JL, Vainchenker W, Constantinescu SN, Lee MA - J. Cell. Mol. Med. (2013)

Effect of JAK and PI3K inhibitions on survival (A) and spleen weight (B) in the JAK2 mutation-driven leukaemia mouse model. Ba/F3 TpoR JAK2 V617F cells (1 × 107) were intravenously inoculated into 8- to 10-week-old female nude mice. After 3 days, mice were treated with either vehicle, GDC0941 alone at 50 mg/kg body weight, ruxolitinib alone at 50 mg/kg body weight, or a combination of both compounds for 12 days. Combination treatment increased survival by 2 days compared with single compound treatment. Combination treatment also reduced spleen weight significantly compared with vehicle-treated mice, or mice treated with GDC0941 alone, or ruxolitinib alone (*P < 0.001 for each comparison). qd: every day, bid: twice a day.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4117552&req=5

fig05: Effect of JAK and PI3K inhibitions on survival (A) and spleen weight (B) in the JAK2 mutation-driven leukaemia mouse model. Ba/F3 TpoR JAK2 V617F cells (1 × 107) were intravenously inoculated into 8- to 10-week-old female nude mice. After 3 days, mice were treated with either vehicle, GDC0941 alone at 50 mg/kg body weight, ruxolitinib alone at 50 mg/kg body weight, or a combination of both compounds for 12 days. Combination treatment increased survival by 2 days compared with single compound treatment. Combination treatment also reduced spleen weight significantly compared with vehicle-treated mice, or mice treated with GDC0941 alone, or ruxolitinib alone (*P < 0.001 for each comparison). qd: every day, bid: twice a day.
Mentions: Female BALB/c nude mice injected with Ba/F3 TpoR JAK2 V617F cells were studied for overall survival and enlargement of spleen (Fig. 5). Tissue samples were collected from mice killed on day 8 and day 14. Spleen weight increased after 8 days of cell implantation, while increase of liver weight was observed by day 14 (Fig. S5A). A progressive increase of Ba/F3 TpoR JAK2 V617F cells in the systemic blood circulation and spleen was observed from day 8 to day 14 (Fig. S5B). An increase of Ba/F3 TpoR JAK2 V617F cells in the bone marrow was observed on day 8 (results not shown). Platelet and red blood cell numbers decreased when compared with the control groups, most likely because of replacement by proliferating Ba/F3 transformed cells (Fig. S5C).

Bottom Line: Synergy was not observed in Bcr-Abl transformed cells.The best JAK2/JAK1 and PI3K inhibitor combination pair (ruxolitinib and GDC0941) reduces spleen weight in nude mice inoculated with Ba/F3 cells expressing TpoR and JAK2 V617F.Our data support the use of a combination of JAK2 and pan-class I PI3K inhibitors in the treatment of MPNs.

View Article: PubMed Central - PubMed

Affiliation: Experimental Therapeutics Centre, Agency for Science Technology and Research, Singapore.

Show MeSH
Related in: MedlinePlus