A small pilot study was conducted in nude mice to evaluate the toxicity of the double sensitizer A-1331852 (A-13) and Palbociclib combinations at a range of doses. A-13 is an oral drug, while Palbociclib can be administered orally or intraperitoneally. To avoid potential trauma associated with multiple daily dosing of these drugs, we administered Palbociclib intraperitoneally daily and A-13 dosed orally daily. We chose a daily oral dose of 25 mg/kg for A-13, as this dose ensures in vivo activity according to data available in the literature (36). Daily administration of A-13 at this dosage did not affect body weight or cause visible signs of toxicity. Palbociclib dosing was first tested at 50 mg/kg ip in combination with A-13 dosed orally daily at 25 mg/kg. Unfortunately, this combined dose of Palbociclib and A-13 caused visible toxicity in the mice, resulting in lowered body temperature, reduced mobility, closed eyes, and/or sudden death. Thus, lower doses of Palbociclib (25 and 12.5 mg/kg) were tested in combination with A-13 (25 mg/kg) (fig. S6). However, these doses were still too toxic, as mice continued to lose weight each day (fig. S6). Within 1 week, mice lost more than 15% of their body weight; the doses 25 and 12.5 mg/kg were therefore too toxic for drug combination studies. A lower dosage (6.25 mg/kg) of Palbociclib was also tested in combination with A-13 at 25 mg/kg dosed orally daily, and an introductory test in which ELP-DRA (30 mg/kg) was added to this combination treatment caused rapid deterioration in body condition over the course of 2 weeks. Change in dosing frequency was also considered, but the half-life of Palbociclib was only a few hours, making this option infeasible (21).

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