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Antimetabolites
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Capecitabine (XelodaTM) is a prodrug of doxifluridine, a fluorinated pyrimidine nucleoside with a cytostatic activity, which is no longer used clinically (Figure 3.11). The pyrimidine ring has a fluorine atom at the 6-position (rather than the 5-position as in 5-FU), a 4-amino group as found in cytarabine, gemcitabine, and gemcitabine but protected as a pentyloxycarbamate. The N1-sugar is modified with a 5′-methyl substituent and a 2′-hydroxy group with an inverted configuration compared to that found in cytarabine. Thus, it is a multiple prodrug of 5-FU designed to be given orally and to be metabolized by a three-enzyme cascade specifically in cancer cells.
Rationale for the use of metronomic chemotherapy in gastrointestinal cancer
Published in Expert Opinion on Pharmacotherapy, 2018
Roberto Filippi, Pasquale Lombardi, Ilaria Depetris, Elisabetta Fenocchio, Virginia Quarà, Giovanna Chilà, Massimo Aglietta, Francesco Leone
In clinics, a small pilot study showed that very low doses of irinotecan (1.4–2.8 mg/m2) were sufficient to increase TSP-1 plasma levels and avoid raising VEGF plasma levels, suggesting a switch toward an antiangiogenic state; furthermore, in the absence of G ≥ 2 toxicity, 20% of patients, who had previously received the same drug with conventional MTD, achieved SD [49]. A phase-II trial, on 45 pretreated or CT-naïve mCRC patients, with low-dose irinotecan (40 mg/m2 weekly for 3 consecutive weeks followed by 1 week of rest), in combination with oral doxifluridine (800 mg/m2, 5 days a week) showed an RR of 35.6%, DCR 73.3%, PFS 6.2 months, and OS 15.1 months [50].
What is the real value of metronomic chemotherapy in the treatment of gastrointestinal cancer?
Published in Expert Opinion on Pharmacotherapy, 2021
Haidar El Darsa, Rola El Sayed, Omar Abdel-Rahman
Capecitabine (Cap), tegafur-uracil (UFUR), doxifluridine (5′-DFUR), and S-1 (tegafur/gimeracil/oteracil) are all oral forms of fluoropyrimidines [3]. Fluoropyrimidines are considered to be the backbone of chemotherapeutic regimens in CRC [3]. Metronomic dosing of these drugs, most commonly Cap (mCap), was evaluated in several trials.
Therapeutic relevance of SOX9 stem cell factor in gastric cancer
Published in Expert Opinion on Therapeutic Targets, 2019
Estefania Carrasco-Garcia, María Álvarez-Satta, Mikel García-Puga, Marcelo Lima Ribeiro, Sara Arevalo, Marcos Arauzo-Bravo, Ander Matheu
Not only the molecular complexity of GC complicates its therapeutic perspective, but also the cellular heterogeneity within tumors. As in other types of cancer, the existence of a subpopulation of cancer stem cells (CSCs), exhibiting unlimited self-renewal and multilineage differentiation potential, has been robustly demonstrated in GC [10,11]. GC stem cells (gCSCs) are thought to be responsible for GC initiation, tumor growth, therapy resistance, tumor recurrence and metastasis [11]. Regarding their origin, it has been postulated that gCSCs derive from the oncogenic transformation of gastric stem cells, which are a diverse group of cells that sustain the fast-renewal of the gastric epithelium, and have been identified at the base and isthmus of the gastric glands [12,13]. Correspondingly, solid evidence for the malignant transformation of gCSCs in gastric carcinogenesis has been reported as a result of multiple genetic and epigenetic events [14,15] and also in response to microenvironmental factors, with demonstrating evidence showing the involvement of H. pylori [16–18]. It is important to highlight that gCSCs exhibit therapy resistance and are responsible for treatment failure, mainly due to their quiescent status and their capacity of self-renewal. Several studies using GC cell lines, cells derived from patients or xenograft models have reported that subpopulations of cells expressing stem cell markers such as SOX9, CD44 or ALDH exhibit resistance to antitumoral agents such as 5-fluorouracil (5-FU), cisplatin, doxorubicin, docetaxel, vinblastine, paclitaxel or doxifluridine, and also against radiation [19–22]. Moreover, in GC patients, residuary tumors after neoadjuvant chemotherapy are enriched in the expression of gCSC markers including LGR5, POU5F1 or BMI-1, being the latter a well-known effector of SOX9, whose knockdown reverses chemoresistance [23,24]. Accordingly, molecular strategies eliciting the inhibition of gCSC markers, including SOX9, lead to the sensitization to cisplatin in CG [19,25]. Importantly, as a consequence of their plasticity, gCSCs are involved in the metastatisation of GC. Thus, in GC patients, the expression of gCSC markers both in primary tumors [26] and in tumor cells disseminated in peripheral blood is associated with a higher risk of recurrence, metastasis and poor outcome [27,28]. Consequently, the identification of the clinical relevance of gCSC biomarkers and regulators is critical to improve our understanding of GC pathobiology, knowledge that taken together with the novel established molecular classifications may allow the development of useful tools for future personalized medical treatments.