An in vitro study of liposomal curcumin: stability, toxicity and biological activity in human lymphocytes and Epstein-Barr virus-transformed human B-cells.

Curcumin is a multi-functional and pharmacologically safe natural agent. Used as a food additive for centuries, it also has anti-inflammatory, anti-virus and anti-tumor properties. We previously found that it is a potent inhibitor of cyclosporin A (CsA)-resistant T-cell co-stimulation pathway.

Plasma and tissue disposition of non-liposomal DB-67 and liposomal DB-67 in C.B-17 SCID mice.

Purpose: DB-67 is a silatecan, 7-silyl-modified camptothecin, with enhanced lipophilicity and increased blood stability of the active-lactone ring. The generation of a liposomal formulation of DB-67 may be an attractive method of intravenous (IV) administration and may maintain DB-67 in the active-lactone form. We evaluated the tissue and plasma disposition of DB-67 lactone and hydroxy acid after administration of non-liposomal (NL) and liposomal (L) DB-67 in severe combined immunodeficient (SCID) mice.

The novel highly lipophilic topoisomerase I inhibitor DB67 is effective in the treatment of liver metastases of murine CT-26 colon carcinoma.

Colorectal carcinoma occurs in 1 of 20 individuals in most developed countries. The relapse after resection with metastatic liver disease is a major cause of death. 7-t-Butyldimethylsilyl-10-hydroxycamptothecin (DB67) has been incorporated into liposomes allowing for intravenous (i.

Analysis of human topoisomerase I inhibition and interaction with the cleavage site +1 deoxyguanosine, via in vitro experiments and molecular modeling studies.

Human topoisomerase I (Top1) plays a pivotal role in cell replication and transcription, and therefore is an important anti-cancer target. Homocamptothecin is a lead compound for inhibiting Top1, and is composed of five conjugated planar rings (A-E). The homocamptothecin E-ring beta-hydroxylactone opens slowly to a carboxylate at pH>7.

Degradation of camptothecin-20(S)-glycinate ester prodrug under physiological conditions.

We have compared the strikingly different decomposition pathways for camptothecin-20(S)-acetate -acetate and camptothecin-20(S)-glycinate in phosphate buffered saline, human plasma and blood. The aliphatic ester analog camptothecin-20(S)-acetate demonstrated excellent stability in the above fluids for many hours with minimal hydrolysis, while the camptothecin-20(S)-glycinate analog (differing solely by the presence of an amino group) underwent rapid and essentially complete decomposition. Reversed-phase high performance liquid chromatography (RP-HPLC) with electrospray ionization-mass spectral (ESI-MS) detection was then used to correlate structural information for camptothecin-20(S)-glycinate decomposition products.

The effect of DB-67, a lipophilic camptothecin derivative, on topoisomerase I levels in non-small-cell lung cancer cells.

Purpose: To determine the in vitro drug sensitivity of two non-small-cell lung cancer cell lines after treatment with the novel lipophilic camptothecin derivative, 7- tert-butyldimethylsilyl-10-hydroxycamptothecin (DB-67), to determine if topoisomerase I protein levels decrease after treatment with DB-67, and to assess the duration and extent of topoisomerase I modulation after DB-67 exposure, in order to provide information about drug resistance that may be useful in determining an appropriate dosing schedule for DB-67.

Methods: The growth inhibition of the non-small-cell lung cancer cell lines A549 and H460 after exposure to DB-67 was evaluated with the MTS assay. A549 and H460 cells were treated for various times with DB-67 and topoisomerase I levels were determined by western blot analysis.

Determination of 9-nitrocamptothecin by precolumn derivatization and its metabolite 9-aminocamptothecin in a biological fluid using reversed-phase high-performance liquid chromatography with fluorescence detection.

A novel insoluble topoisomerase I inhibitor, 9-nitrocamptothecin (9-NC), is in advanced stages of clinical development and has been used to treat a diverse array of tumor types, including breast, ovarian, pancreatic and haematological malignancies. We have established a sensitive high-performance liquid chromatography method using fluorescence detection for the quantitation of 9-NC. Non-fluorescent 9-NC is converted to fluorescent 9-aminocamptothecin (9-AC) via a one-step pre-column derivative reaction.

A versatile prodrug approach for liposomal core-loading of water-insoluble camptothecin anticancer drugs.

We describe a versatile prodrug strategy for loading the liposomal lumen with water-insoluble camptothecins. The procedure involves conversion of an active camptothecin analogue to a 20-OR omega-aminoalkanoanic ester prodrug in which R = CO[CH(2)](n)()NH(2) and n = 1-3. The basic amino group of the prodrug serves three roles.

Synthesis and evaluation of a novel E-ring modified alpha-hydroxy keto ether analogue of camptothecin.

The synthesis of a novel E-ring modified keto ether analogue of camptothecin and homocamptothecin by the cascade radical annulation route is reported. The analogue, Du1441, is an isomer of homocamptothecin, but includes the alpha-hydroxy carbonyl functionality that camptothecin possesses and homocamptothecin lacks. Despite these similarities, the new keto ether analogue is inactive in cell assays, and implications for the structure/activity relationship are discussed.