liquid chromatography and mass spectrometry to show the presence of CNddC in hydrolysates 
of DNA isolated from cells following CNDAC treatment method, indicating that B elimination occurs in intact cells. The analog showed broad spectrum activity against tumor cell lines and also in the P388 leukemia mouse model. CNDAC was more successful than cytarabine in some human tumor cell lines derived from lung, stomach and osteosarcoma and showed outstanding activity against tumor cell lines refractory to cytarabine. Even so, the orally administered prodrug was much more strong against human tumor xenografts than CNDAC or 5 fluorouracil. It was also effective against various human organ tumor xenografts more than a wider dose range and with fewer toxicities.
CS 682 was also successful against P388 human leukemia cells resistant to a variety of other agents such as mitomycin C, large-scale peptide synthesis, 5 fluorouracil and cisplatin in syngeneic mice. Utilizing highresolution magnetic imaging, huge-scale peptide synthesis Wu et al. demonstrated that CS 682 delayed the growth of orthotopically implanted AX3488 liver tumors, and also delayed their meta static behavior. The metastatic behavior of an orthotopic model of pancreatic carcinoma was delayed, and general survival of the mice was prolonged by CS 682. A liposomal formulation of CNDAC showed activity against Meth A sarcoma bearing mice when injected intravenously. The antitumor activity of the liposomally encapsulated formulation was a lot more potent than that of the parent drug suggesting that the liposomal preparation improved therapeutic efficacy although at the exact same time decreasing toxicity.
Sapacitabine in blend with histone deacetylase inhibitors induced an enhance in apoptosis and demonstrated considerable benefit compared with the single agent treatments both in vitro and in xenografts of the MV4 11 myeloid leukemia. The encouraging activities in preclinical models provided rationale for clinical trials of the bioavailable prodrug formulation. Two multicenter Phase I clinical trials of CS 682 in patients with advanced sound tumors have been reported. Two schedules of oral administration were investigated, once every day for 5 days for 4 weeks and once every day on days 1, 3 and 5 for 4 weeks. In the former trial, the drug was investigated in 47 patients with twelve doses that ranged between 1. and 67 mg/m2/dose.
The dose limiting toxicity was neutropenia. No aim tumor responses have been accomplished although 11 sufferers skilled stable illness. The advised Phase II dose was 40 mg/m2/dose. In the second trial, CS 682 was given three times per week for 4 consecutive weeks followed by a 2 week rest period. Eleven doses that ranged PARP from 1. 5 to 120 mg/m2/day have been investigated. Important hematologic toxicities occurred at dose ranges amongst 90 and 120 mg/m2/day. Six individuals seasoned stable condition. The suggested Phase II doses were schedule dependent 30 mg/m2/dose and 160 mg/ m2/dose. Non hematologic toxicities rarely exceeded grade 1 or 2 according to the NCI typical toxicity criteria. Every of these trials was complemented by comprehensive pharmacokinetic investigations.
These scientific studies demonstrated the bio availability of CS 682. Administered orally at the greatest tolerated dose of 40 mg/m2 on the day-to-day instances 5 days schedule, the peak plasma concentration of 4. 1 _ 1. 2 ng/ml was observed at 2. h. The Cmax GABA receptor of CNDAC of 27 _ 14 ng/ml was accomplished at 2.