sulindac and Carcinoma-in-Situ

Pancreatic cancer remains one of the deadliest diseases, with limited surgical and treatment options. Two targets of interest include the transcription factor nuclear factor-κB and cyclooxygenase-2, which are constitutively activated and overexpressed, respectively, in human pancreatic adenocarcinoma. We have previously shown that dimethylaminoparthenolide (DMAPT), a bioavailable nuclear factor-κB inhibitor, and the cyclooxygenase inhibitors sulindac and celecoxib have potential chemotherapeutic efficacy. The current study evaluates the efficacy of intervention with DMAPT and sulindac in the LSL-Kras(G12D);Pdx-1-Cre genetically engineered mouse model. Gemcitabine, traditionally a chemotherapeutic agent, has relatively low toxicity; thus, combinations with low-dose gemcitabine were also explored.. LSL-Kras(G12D);Pdx-1-Cre mice at 7 months of age were randomized into placebo, DMAPT (40 mg/kg per day), sulindac (20 mg/kg per day), gemcitabine (50 mg/kg twice weekly), and combination treatment groups. After 3 months of treatment, the mice were killed.. The percentage of normal pancreatic ducts was significantly increased by the combinations of DMAPT/sulindac, DMAPT/gemcitabine, sulindac/gemcitabine, and DMAPT/sulindac/gemcitabine compared to placebo. Additionally, the percentage of mouse pancreatic intraepithelial neoplasia-2 lesions was significantly decreased by DMAPT/gemcitabine.. Intervention with DMAPT and sulindac in combination with gemcitabine may delay or prevent progression of premalignant pancreatic lesions in the LSL-Kras(G12D);Pdx-1-Cre mouse model of pancreatic cancer.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Carcinoma in Situ; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cytokines; Disease Progression; Genes, p53; Mice; Mice, Transgenic; Mutation; NF-kappa B; Pancreatic Neoplasms; Proto-Oncogene Proteins p21(ras); Sesquiterpenes; Sulindac

Patients with chronic lymphocytic leukemia (CLL) often have a protracted course. However, all these patients are immunosuppressed and may have a high incidence of cutaneous malignancies.. To determine if combination therapy using topical imiquimod cream 5% and the oral cyclooxygenase (COX) inhibitor are useful in the therapy of squamous cell carcinoma in situ (SCC in situ)/Bowen's disease in patients with long-standing CLL.. Five CLL patients with head and neck cutaneous SCC in situ, which met criteria for Bowen's disease, were treated with topical 5% topical imiquimod cream and an oral COX inhibitor, sulindac 200 mg twice a day.. All patients showed clinical resolution and histologic clearing of the tumors after 16 weeks of therapy.. The local immune modulator, 5% imiquimod, in combination with a COX inhibitor, with its many potential antitumor effects may stimulate the innate and possibly the adaptive immune responses to clear these malignancies.

Topics: Adjuvants, Immunologic; Administration, Topical; Aged; Aminoquinolines; Antineoplastic Agents; Bowen's Disease; Carcinoma in Situ; Cyclooxygenase Inhibitors; Drug Therapy, Combination; Female; Humans; Imiquimod; Immunosuppression Therapy; Immunotherapy; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Neoplasms, Second Primary; Ointments; Skin Neoplasms; Sulindac