Background and Rationale: Although the majority of patients with endometrial cancer (EC) are diagnosed early when disease is confined in the uterus and prognosis is excellent, there is a subset of patients with dismal prognosis. Carboplatin and paclitaxel is the standard chemotherapeutic regimen for EC. Given that response to chemotherapy impacts disease prognosis, especially in advanced, recurrent and metastatic disease, novel chemotherapeutic agents with improved safety profile are necessary to improve response rates and outcomes in these patients. Quinacrine (QC) is an inexpensive antimalarial drug with a predictable safety profile which recently surfaced as a promising anticancer agent thought to be associated with decreased risk of developing chemo-resistance through targeting multiple pathways simultaneously.
Objective: To generate preclinical data on the effect of QC in inhibiting tumorigenesis in EC both in vitro and in vivo as well as explore its role as an adjunct to standard chemotherapy in vivo in an EC mouse xenograft model.
Methods: Five different EC cell lines (Ishikawa, Hec-1B, KLE, ARK-2, and SPEC-2) representing different histologies, grades of EC, sensitivity to cisplatin and p53 status were used for the in vitro studies. MTT and colony formation assays were used to examine QC’s ability to inhibit cell viability in vitro. Drug combination studies were performed and the Chou-Talalay methodology was employed in order to examine synergism between QC and cisplatin, carboplatin or paclitaxel. A cisplatin-resistant EC subcutaneous mouse xenograft model was used in order to explore QC’s anticancer activity in vivo and assess its role as maintenance therapy.
Results: QC exhibited strong synergism in vitro when combined with cisplatin, carboplatin or paclitaxel with the highest level of the synergism being observed in the most chemo-resistant EC cell line. Neither QC monotherapy nor standard chemotherapy significantly delayed tumor growth in the mouse xenografts. Co-administration of QC with standard chemotherapy significantly augmented the antiproliferative ability of these chemotherapeutic agents as evidenced by the significant decrease in tumor burden. Combination treatment was associated with a 14-week prolongation of median survival compared to standard chemotherapy alone. Maintenance therapy with QC following standard chemotherapy was proven superior to standard chemotherapy as it resulted in long-term stabilization of disease evidenced by lack of significant tumor progression and further prolongation of overall survival. QC treatment alone, in combination with standard chemotherapy or as maintenance therapy was well-tolerated and was not associated with weight loss compared to control mice. A yellow skin discoloration was noted during active treatment with QC which was entirely reversible within a few days upon discontinuation of treatment.
Conclusions: QC exhibited significant antitumor activity against EC cell lines in vitro and was successful as maintenance therapy in chemo-resistant EC mouse xenografts. This preclinical data suggest that QC may be an important adjunct to standard platinum-based chemotherapeutic regimens for patients with recurrent EC.
|Advisor:||Dowdy, Sean C.|
|Commitee:||Breitkopf, Daniel M., Cliby, William A., Daftary, Gaurang S., Shridhar, Vijayalakshmi (Viji), Weaver, Amy|
|School:||College of Medicine - Mayo Clinic|
|Department:||Clinical and Translational Science|
|School Location:||United States -- Minnesota|
|Source:||MAI 55/04M(E), Masters Abstracts International|
|Keywords:||Chemo-resistance, Endometrial cancer, Maintenance therapy, Quinacrine|
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