Preliminary data of the antipancreatic tumor efficacy and toxicity of long-circulating and pH-sensitive liposomes containing cisplatin.

PURPOSE: Pancreatic cancer is the fourth most common cause of cancer-related death in the USA. This is mainly because of the chemoresistance of this type of tumor; thus, the development of novel therapeutic modalities is needed. METHODS: Long-circulating and pH-sensitive liposomes containing cisplatin (SpHL-CDDP) were administered systemically into pancreatic tumor-bearing mice for a period of 14 days. The antitumor efficacy and toxicity of this new treatment method on the basis of cisplatin-loaded liposomes was compared with the classical free-CDDP method. Tc-HYNIC-ßAla-bombesin(7-14) tumor uptake and histopathologic findings were used to monitor and compare the two treatment modalities. RESULTS: The antitumor activity of SpHL-CDDP treatment was shown by (a) decrease in tumor volume, (b) development of tumor necrotic areas, and (c) decrease in Tc-HYNIC-ßAla-bombesin(7-14) tumor uptake. Toxicity was evaluated by the development of inflammation and necrotic areas in the kidneys, liver, spleen, and intestine: toxic effects were greater with free-CDDP than SpHL-CDDP. CONCLUSION: SpHL-CDDP showed significant antitumor activity in pancreatic cancer-bearing mice, with lower toxicity in comparison with free-CDDP.

Synthesis of novel 2,3,4-trisubstituted-oxazolidine derivatives and in vitro cytotoxic evaluation.

We have previously reported the discovery of cytotoxic and pro-apoptotic hit compound 1,1-dimethylethyl (S)- 2,2-dimethyl-4-[(3-nitrophenoxy)methyl]-3-oxazolidinecarboxylate 1 against leukemia cells. In the present work we describe the synthesis of 25 derivatives of this hit varying the substituent at ring or stereochemistry of the oxazolidine ring and evaluated them against human cancer cells lines. Six compounds exerted significant activity against HL60 promyelocytic leukemia cells with IC50 in low micromolar range (4-18 µM) and three compounds displayed activity against MDA-MB231 breast cancer cells (25-37 µM). In vitro cytotoxicity on normal cells PBMC (human peripheral blood mononuclear cells) was also evaluated. Compounds 7e (p-NO2, S) and 7m (p-COOCH3, S) showed good antiproliferative activity against HL60 (4 and 5 µM) and MDA-MB231 (37 and 25 µM) without affecting lymphocyte proliferation in PBMC, indicating low toxicity to normal cells. Besides, compound 7e induced DNA fragmentation on about 100% of HL60 cells at 50 µM. In this case, it was more potent than 7m and lead 1. This indicated that compound 7e has a great pro-apoptotic potential.