In vitro activity of liposomal N4octadecyl-1-[beta]-D-arabinofurano-sylcytosine (NOAC), a new lipophilic derivative of 1-[beta]-D-arabino-furanocylcytosine on biopsized clonogenic human tumor cells and hematopoietic precursor cells

Byline: R.A. Schwendener (1), K. Friedl (2), H. Depenbrock (2), H. Schott (3), A.-R. Hanauske (2) Keywords: lipophilic ara-C derivative; liposomes; clonogenic growth; human tumors; in vitro activity Abstract: N.sup.4-octadecyl-1-[beta]-D-arabinofuranosylcytosine (NOAC) is a new lipophilic derivative of1-[beta]-D-arabinofuranosylcytosine(ara-C) with potent antitumor activityagainst leukemias and solid tumors. In thisstudy the activity of NOAC against freshlyexplanted clonogenic cells from humantumors was determined and compared withconventional antitumor agents. NOAC wasused in two liposomal preparations, astable lyophilized and a freshly preparedliquid formulation. Both formulationsinhibited tumor colony formation equally ina concentration-dependent fashion in bothshort- (1h) and long-term (21-28 d)exposure experiments. NOAC (100 uM,long-term exposure) had a significantlybetter activity compared to the clinicallyused drugs cisplatin, doxorubicin,5-fluorouracil, gemcitabine, mitomycin Cand etoposide. The comparison of NOAC withara-C in the long-term exposure experimentshowed that ara-C was more effective at 4and 10 uM, whereas at 1 and 100 uMthere was no difference between the twodrugs. NOAC was less toxic in ahematopoietic stem cell assay than ara-Cand doxorubicin by factors ranging from 2.5to 200, indicating that this drug is welltolerated at high doses. The antitumoractivity of NOAC (NSC 685096) was confirmedby the NCI in vitro drug screening programwhere the drug was found to be activeagainst several types of human tumors.Further development of NOAC in phase IIstudies is warranted. Author Affiliation: (1) Department of Pathology, Division of Cancer Research, University Hospital, Zurich, Switzerland (2) Division of Hematology and Oncology, Department of Medicine, Technische Universitat Munchen, Munich, Germany (3) Institute of Organic Chemistry, University of Tubingen, Germany Article History: Registration Date: 11/10/2004