Abstract 1857: Effects of long-term chloroquine chemotherapy in a preclinical model of PTEN-deficient prostate cancer

Abstract

Abstract Chloroquine (CQ) and its derivative hydroxychloroquine are drugs that have been used to treat malaria and rheumatism. These drugs are also capable of producing antitumor effects in preclinical cancer models. In addition to mediating antitumor effects by impairing autophagy in certain cancer cells types, these agents have also been shown to effect antitumor responses independent of autophagy inhibition. Treatment strategies using CQ and its derivative alone or in combination with other anticancer drugs are being considered for clinical applications. However, the safety and long-term effects of CQ therapy for the treatment of cancers are unknown. In this study, we investigated the safety and efficacy of long-term CQ therapy in a PTEN-deficient model of prostate cancer. Twenty-eight-week-old tumor-bearing PTEN conditional knockout mice (PSA-CRE+/PTENf/f) were treated with CQ in the drinking water. Based on daily water consumption, the daily oral dose was adjusted to 100 mg/kg in distilled water. Timed sacrifices were scheduled 2, 4, 8, 16 and 32 weeks after the initiation of treatments and subset of mice was used for survival analysis. Mice receiving CQ were healthy in appearance and normal in demeanor. Compared to controls, mice receiving CQ began to exhibit lower body weights over the course of treatment beginning at 5 weeks after the initiation of treatment. At the completion of the study, mice receiving CQ averaged 27.3 grams of bodyweight compared to 33.8 grams in the control group (P<0.001). However, chronic treatment with CQ for 32 weeks inhibited tumor burden by 18.4% (P = 0.0118). For the long-term survival studies, median survival for control and CQ treated mice was 83.4 and 82.0 days, respectively (P = 0.782). Bodyweights of CQ mice were significantly reduced (44.8% of control, P = 0.029). Tumor burden at time of death decreased from 15.9% ±5.9 of bodyweight in control mice to 2.5% ±0.6 in CQ-treated mice (P<0.05). In summary, our studies show that long-term chronic administration of CQ was capable of inhibiting growth of PTEN-deficient tumors, however, CQ was poorly tolerated by mice and did not improve overall survival. Thus, caution should be exercised to carefully assess the safety and tolerability of this drug when using it long-term in human clinical trials. Citation Format: Kazuhiro Yoshikawa, Marco A. De Velasco, Yurie Kura, Naomi Ando, Emiko Fukushima, Yutaka Yamamoto, Yuji Hatanaka, Takashi Oki, Nobutaka Shimizu, Kazuhiro Yoshimura, Kazuto Nishio, Hirotsugu Uemura. Effects of long-term chloroquine chemotherapy in a preclinical model of PTEN-deficient prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1857. doi:10.1158/1538-7445.AM2015-1857