Determination of minimum effective dose and optimal dosing schedule for liposomal curcumin in a xenograft human pancreatic cancer model.
BACKGROUND
Curcumin is a food chemical present in tumeric (Curcuma longa) that has pharmacological activity to suppress carcinogenesis and inhibits multiple signaling pathways such as nuclear factor kappaB (NF-kappaB), cyclooxygenase-2 (Cox-2) and interleukin-8 (IL-8). Oral curcumin has poor oral bioavailability limiting its clinical activity; however, a patent pending liposomal formulation of curcumin was developed to improve drug delivery and has demonstrated activity in multiple cancers. This study was designed to determine the minimum effective dose (MED) as well as the optimal dosing schedule of liposomal curcumin in a xenograft mouse model of human pancreatic cancer.


METHODS
The MED determination and optimal schedule was evaluated in female athymic nude mice injected subcutaneously with MiaPaCa-2 cells. Dosing was initiated at an average tumor size of 5mm. For the MED, mice were treated with the following dose levels of liposomal curcumin: no treatment, liposome only, 1 mg/kg, 2 mg/kg, 5 mg/kg, 10 mg/kg, 20 mg/kg and 40 mg/kg given by tail vein injection three times weekly for 28 days. For the optimum dosing schedule, three additional schedules were evaluated and compared to the control of three times weekly; daily (five days per week), every four days, and weekly for 28 days. All mice were weighed and tumor measurements taken three times weekly to evaluate toxicity and efficacy.


RESULTS
The 20 mg/kg dose had the greatest decrease in tumor growth at 52% decrease in tumor growth when compared to no treatment control mice. MED was determined to be 20 mg/kg and was used for the optimal dosing schedule determination. Daily dosing and three times per week dosing had greater inhibition of tumor growth with no discernable difference than once weekly or every 4 day dosing. No toxicity was observed at any dose or schedule.


CONCLUSIONS
The MED for liposomal curcumin is 20 mg/kg given once daily three times per week to achieve optimal tumor growth inhibition. This was dose recommended for additional preclinical studies to define safety and tolerability of liposomal curcumin in rat and dog models.
Mach
Claire M
CM
Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas 77230-1439, U.S.A.
Mathew
Lata
L
Mosley
Scott A
SA
Kurzrock
Razelle
R
Smith
Judith A
JA
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D003474:Curcumin / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008081:Liposomes; D051379:Mice; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D008081:Liposomes; D003474:Curcumin