Forodesine

Biological Activity

Forodesine (BCX-1777) is a highly potent and orally active purine nucleoside phosphorylase (PNP) inhibitor with IC₅₀ values ranging from 0.48 to 1.57 nM for human, mouse, rat, monkey and dog PNP. Forodesine is a potent human lymphocyte proliferation inhibitor. Forodesine could induce apoptosis in leukemic cells by increasing the dGTP levels.

Mouse T-cell models
Briefly, mice were sensitized with 25 ul of 0.5% 2,4-dinitrofluorobenzene(DNFB) in acetone/olive oil (4:1), which was paintedonto the shaved abdominal skin on days 0 and 1 (1 hafter dosing). Mice were dosed once a day(q.d.) with either vehicle, BCX-1777 (30 mg/kg, orally) or cyclosporin A (50 mg/kg, intraperitoneally) for 6 days. On day 5, the right ears of mice were painted with 20 ul of 0.3% DNFB in acetone/olive oil(4:1), and 24 h later, the thickness of the ears were measured with a vernier caliper.
The graft vs. host (GVH) reaction was evaluatedin mice by measuring the degree of splenomegaly induced by the intraperitoneal injection of male hy-brid mice with splenocytes from the parental strain (C57BL/6) as described by Roudebush and Bryant. Briefly, spleens were removed aseptically from C57BL/6 mice and dissociated in polypropylene mesh screens. After lysis with an ammonium chloride buffer, splenocytes were washed twice in modified HBSS and were injected i.p. (2 x10^8 cells/ml) in hybrid mice in a volume of 0.5ml/mouse on day 0. Hybrid mice were dosed with BCX-1777 (30 mg/kg, orally), or cyclosporin A (50mg/kg, i.p.) for 10 days; controls received HBSS orparental spleen injections at day 0 and were dosed with vehicle either i.p. or orally. Spleens were removed and weighed and the results were recorded as a ratio of spleen weight to body weight.

Hu-PBL SCID mouse model
SCID mice were pretreated 1 day prior to hu-PBL injection with a single dose of anti-ASGM1 antibodies. Anti-ASGM1 consists of rabbit polyclonal antibodies, which recognize murine NK cells, and depletes NK activity. Immediately before hu-PBL engraftment, SCID mice were irradiated. A dose of 3 Gy gamma-radiation was administered from a 137Cs  source. Human lymphocytes for engraftment in SCID mice were isolated from buffy coats or from whole blood of volunteer donors. The hu-PBLs were isolated by Ficoll–Hypaque centrifugation and injected i.p. (3.0–5.0x10^7 PBLs/mouse) into SCID mice under sterile conditions. The experimental animals were pretreated for 5 days with BCX-1777 (20 mg/kg/day, b.i.d.) in 0.5% carboxymethylcellulose (CMC) to elevate the dGuo levels. Control animals were treated with 0.5% CMC. The life span of the control and experimental animals were compared.

Chemical Information

Molecular Weight	266.25
Formula	C11H14N4O4
CAS Number	209799-67-7
Form	Solid
Solubility (25°C)	DMSO 90 mg/mL
Storage	Powder          -20°C   3 years ;  4°C   2 years In solvent       -80°C   6 months ;  -20°C   1 month

References

[1] Tamara Davenne, et al. Cell Rep. SAMHD1 Limits the Efficacy of Forodesine in Leukemia by Protecting Cells against the Cytotoxicity of dGTP

[2] Shinichi Makita, et al. Onco Targets Ther. Forodesine in the treatment of relapsed/refractory peripheral T-cell lymphoma: an evidence-based review

[3] Daniel J Lewis, et al. Expert Opin Investig Drugs. Forodesine in the treatment of cutaneous T-cell lymphoma