Improving Gemcitabine-Mediated Radiosensitization Using Molecularly Targeted Therapy: A Review

Abstract

In the last three decades, gemcitabine has progressed from the status of a laboratory cytotoxic drug to a standard clinical chemotherapeutic agent and a potent radiation sensitizer. In an effort to improve the efficacy of gemcitabine, additional chemotherapeutic agents have been combined with gemcitabine (both with and without radiation) but with toxicity proving to be a major limitation. Therefore, the integration of molecularly targeted agents, which potentially produce less toxicity than standard chemotherapy, with gemcitabine radiation is a promising strategy for improving chemoradiation. Two of the most promising targets, described in this review, for improving the efficacy of gemcitabine radiation are epidermal growth factor receptor and checkpoint kinase 1.Gemcitabine was first introduced into the clinic as a chemotherapeutic agent nearly 3 decades ago. Since then, both laboratory and clinical investigations have shown gemcitabine to be a potent radiation sensitizer. In this review, we will begin with a discussion of gemcitabine biochemistry and its mechanisms of interaction with radiation, highlighting observations that may lead to improving the design of clinical trials combining gemcitabine with radiation. Previous attempts to improve the efficacy of gemcitabine radiotherapy have included the addition of other chemotherapeutic agents (1 -3) such as cisplatin (4) and oxaliplatin (5). More recent studies have focused on the addition of molecularly targeted therapies, to gemcitabine, and radiation (6, 7). In this review, we will present our rationale for integrating checkpoint kinase 1 (Chk1)-and epidermal growth factor (EGFR) molecularly targeted agents with gemcitabine radiation therapy. Gemcitabine Biochemistry and RadiosensitizationThe antitumor activity of gemcitabine depends on a series of sequential phosphorylations. In the first rate-limiting step, deoxycytidine kinase converts gemcitabine to the monophosphorylated metabolite, dFdCMP [this has motivated the study of fixed-dose-rate infusion (10 mg/m 2 /min), which increases intracellular metabolites compared with bolus treatment (8, 9), but in the majority of trials, does not significantly improve survival (10)]. Subsequent phosphorylations lead to the accumulation of gemcitabine diphosphate and triphosphate (dFdCDP and dFdCTP) that are both active metabolites (Fig. 1). Whereas dFdCTP can interfere with DNA synthesis by competing with endogenous dCTP for misincorporation into replicating DNA, dFdCDP is a potent inhibitor of ribonucleotide reductase, reducing the synthesis of deoxynucleoside triphosphates, primarily dATP (in solid tumor cells).

Statins inhibit Akt/PKB signaling via P2X7 receptor in pancreatic cancer cells

“…Statins have been shown to 17 reduce NFB activation by inhibiting prenylation [36][37] and our data show that in Capan-2 cells NFB was reduced. In the same time phosphorylation of Raf and MEK were affected, which can be explained by an inhibited prenylation of Ras [32][33][34][35][36][37][38][39][40][41]. The reason why Panc-1 and MIA PaCa-2 cells were less sensitive to these effects remains to be studied.…”

“…Gemcitabine is the current standard chemotherapeutic drug for treatment of pancreatic cancer but with minor benefit [37]. However, we found that in combination treatment, show that silencing of P2X7 with siRNA prevented the effect of atorvastatin on cell proliferation.…”

Gemcitabine-Based Chemoradiation in the Treatment of Locally Advanced Head and Neck Cancer: Systematic Review of Literature and Meta-Analysis

“…The rationale behind the latter approach is based on the knowledge that gemcitabine activates checkpoint kinases, which regulate the cell cycle progression. Preclinical studies using selective knockout of checkpoint kinase 1 in pancreas tumor cell lines confirmed the theoretical background [71]. With EGFR inhibitors, the research has advanced much further.…”

Gemcitabine Inhibits Murine Head and Neck Squamous Cell Carcinoma Growth via Proteasome-Dependent Degradation of Chk1 Leading to Cell Cycle Arrest and Apoptosis

“…For more than a decade, gemcitabine has been used for the treatment of metastatic pancreatic cancer [14]. Recent clinical studies have shown favorable therapeutic responses and toxicity profiles of gemcitabine treatment in patients with advanced HNSCC [15,16].…”

“…Recent clinical studies have shown favorable therapeutic responses and toxicity profiles of gemcitabine treatment in patients with advanced HNSCC [15,16]. Gemcitabine increases tumor cell sensitivity to radiation-induced apoptosis and hence is used as a radiation sensitizer in solid malignancies [14,17,18]. Antitumor activity of gemcitabine is mediated by multiple mechanisms dependent upon tumor types [19][20][21].…”