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Anti-Cancer Agents from Natural Sources
Published in Rohit Dutt, Anil K. Sharma, Raj K. Keservani, Vandana Garg, Promising Drug Molecules of Natural Origin, 2020
Debasish Bandyopadhyay, Felipe Gonzalez
Three other campotothecin derivatives contain anticancer activities which include belotecan, lurtotecan, and exatecan. Belotecan has been tested by Choi et al. (2010) in a phase II trialalong with carboplatin (combination therapy) to assess its anticancer effect on patients that suffer from recurrent ovarian cancer. The clinical trial included 38 patients and became successful with an overall response rate of 57.1% and comprehensive response rate of 20%. Lurtotecan is highly water-soluble and due to this most research conducted on it focused on delivering the drug through liposomal formulation, NX211. Studies (Desjardins et al., 2001) on mice-bearing KB cancer cells determined that lurtotecan delivered in NX211 could improve the chances of drug-to-tumor contract. Exatecan, another analog of camptothecin, has a useful anticancer effect on advanced peritoneal, ovarian, and tubal cancer when novel anticancer agents such as topotecan, taxane, and cis-platin failed (Verschraegen et al., 2004). The phase II clinical study demonstrated its effectiveness when patients administered a daily dose in 5 times a day continuously every 3 weeks. Figure 5.6 provides the structure of anticancer campotothecin. Anticancer effect of a few significant natural and semi-synthetic drugs is summarized in Table 5.1.
Application of Phytodrug Delivery in Anticancer Therapy
Published in Madhu Gupta, Durgesh Nandini Chauhan, Vikas Sharma, Nagendra Singh Chauhan, Novel Drug Delivery Systems for Phytoconstituents, 2020
Camptothecins (CPTs), which are derived from the bark and stem of Chinese ornamental tree Camptotheca accuminata with broad-spectrum anticancer activity, have become the third largest anticancer drugs worldwide (Han, 1994).They are characterized by their specific inhibition of enzyme topoisomerase I, which would lead to the separation of DNA strands prior to transcription and replication (Berti et al., 2013, Chaudhuri et al., 2012, Huang et al., 2012, Tomicic and Kaina, 2013). CPT was first recognized in the mid-1960s by Wall et al. (1966); however, its early promise was blighted by poor solubility as well as unpredictable side effects, preventing CPT from being approved (Venditto and Simanek, 2010). Therefore, a series of CPT derivatives have been developed subsequently via chemical manipulation, mainly including topotecan, irinotecan, belotecan, exatecan, gimatecan, and karenitecan, which have been proverbially applied in the treatment of numerous tumors, including ovarian cancer, lung cancer, breast cancer, pancreatic cancer, metastatic colorectal cancer, glioblastoma, small cell carcinoma, etc. (Bissinger et al., 2015, Cremolini et al., 2015, Kamisawa et al., 2016, Kim et al., 2013, Liu et al., 2015a, Mulholland and Wu, 2016, Wan et al., 2012, Wang-Gillam et al., 2016). The plant source of CPTs, the chemical structure of camptothecin, and representative anticancer alkaloids derived from CPT are shown in Figure 9.3c. It was found that chemotherapy with oral topotecan achieved prolonged survival and improved quality of life for patients with relapsed small-cell lung cancer (SCLC) (O’Brien et al., 2006). It was also shown that, as the first-line therapy for patients with metastatic colorectal cancer, the combination of irinotecan/5-FU/LV prevailed over 5-FU/LV alone, accompanied by enhanced tumor control as well as prolonged survival (Saltz et al., 2001). Besides, it has been shown that belotecan combined with etoposide presented significant activity for platinum-resistant or heavily pretreated ovarian cancer patients (Hwang et al., 2012), and similar activity has also been demonstrated via the combination of belotecan and carboplatin (Choi et al., 2011). Moreover, belotecan showed promising efficacy for glioblastoma combined with cliengitide (Kim et al., 2013), also prospective for small-cell lung cancer as the second-line therapy (Chan and Coward, 2013, Rhee et al., 2011) or as the first-line chemotherapy when combined with cisplatin (Hong et al., 2012).
Therapeutic modalities in small cell lung cancer: a paradigm shift after decades of quiescence
Published in Expert Opinion on Pharmacotherapy, 2022
Rola El Sayed, Haidar El Darsa
Belotecan is a semi-synthetic camptothecin analogue that blocks topoisomerase I, causing lethal DNA breaks, and inducing tumor cell apoptosis [92]. It was investigated in second-line setting in patients with ES-SCLC post failure of platinum-based chemotherapy in a 1:1 ratio compared to topotecan in a phase IIb trial, that demonstrated numerical improvement of ORR (33 vs 21%, p = 0.09), as well a DCR (85 vs 70%, p = 0.03), and a longer mOS (13.2 vs 8.2 months, HR = 0.69, 95% CI 0.48–0.99), with an acceptable safety profile [93]. However, after a first-line combination phase III trial of Belotecan with cisplatin compared to etoposide and cisplatin showed no difference in response, but with increased toxicity, specifically hematologic toxicity, belotecan disappeared from the field [94].