Purushottamachar Puranik - Murine toxicology and pharmacokinetics evaluation of retinoic acid metabolism blocking agent (RAMBA), VN/12-1.

Version 1

      Publication Details (including relevant citation   information):

      Cancer Chemother   Pharmacol. 2012, 70(2), 339-44. PMID   22580781

        Godbole AM,   Purushottamachar P,   Martin MS,   Njar VC.

      Abstract:

      PURPOSE:

      Novel retinoic acid metabolism blocking agent (RAMBA), VN/12-1,   is a highly potent anti-cancer agent that induces autophagy. Its   combination with autophagy inhibitor chloroquine (CHL) has been   shown to synergistically enhance apoptosis in breast cancer   cells. The purpose of this study was to determine the toxicity   and pharmacokinetic profile of VN/12-1 and its combination with   CHL.

      METHODS:

      Preliminary toxicology of VN/12-1 was determined using female   SCID mice (n = 4 for each group). ATRA was used for comparison.   We selected four different doses of VN/12-1 and ATRA. Two of the   doses were low and less frequent (2.5 and 5 mg/kg twice a week),   and the remaining doses were high and more frequent (10 and 20   mg/kg every day). The dose of CHL was 50 mg/kg twice a week. For   pharmacokinetic (PK) study, 20 mg/kg of VN/12-1 was injected   subcutaneously (s.c.) into the mice, and their plasma was   collected at various intervals (n = 2) and analyzed by HPLC.

      RESULTS:

      The lower and less frequent doses of VN/12-1 and ATRA were found   to be least toxic. However, high and more frequent doses of these   compounds were toxic to the mice. PK results showed that VN/12-1   has a half-life of 6 h. The area under the curve (AUC) for   VN/12-1 was 83.78 h μg/ml.

      CONCLUSIONS:

      VN/12-1 and ATRA are non-toxic when used as 5 mg/kg twice a week   as single agents or in combination with CHL. The favorable PK   properties of VN/12-1 can potentially be used for its further   advanced pre-clinical and clinical development.

      Address (URL): http://www.ncbi.nlm.nih.gov/pubmed/22580781