Possible Pathways of Capecitabine-Induced HandâFoot Syndrome

Review pubs.acs.org/crt

Possible Pathways of Capecitabine-Induced Hand−Foot Syndrome Yan Lou,† Qian Wang,† Jinqi Zheng,‡ Haihong Hu,§ Lin Liu,† Dongsheng Hong,*,† and Su Zeng*,§ †

The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 QingChun Road, Hangzhou, Zhejiang 310000, People’s Republic of China ‡ Zhejiang Institute for Food and Drug Control, Hangzhou, Zhejiang 310004, People’s Republic of China § Laboratory of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, People’s Republic of China

ABSTRACT: Capecitabine, an oral prodrug of 5-fluorouracil, inhibits DNA synthesis and has received FDA approval for treatment of metastatic colorectal and breast cancers. Hand−foot syndrome (HFS) is a serious dose-limiting toxicity and the most frequently reported side effect of capecitabine. Because of the lack of knowledge about the causative mechanism of HFS, scarce information is available for effective treatment or prevention. Data are based on published literatures and reports available from the HFS development program database. The purpose of this Review is to provide information regarding definition, clinical manifestation, and the possible mechanisms of HFS induced by capecitabine. Ethnic variations in the clinical presentation of HFS warrant further attention. Several physiological and pharmacological mechanisms have been investigated, such as cyclooxygenase (COX) inflammatory-type reaction, accumulation of capecitabine metabolites, and enzymes and transporters involved in the metabolism and absorption. Although current studies describe the possible mechanisms of HFS induced by capecitabine, much remains to be determined. It appears from this scientific evidence that additional study is needed to determine the effect of skinmediated metabolism in the possible mechanism of HFS induced by capecitabine.

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CONTENTS

1. INTRODUCTION

1. Introduction 2. Definition and Clinical Presentation of Hand− Foot Syndrome 3. Possible Pathways of Capecitabine-Induced HFS 3.1. COX Inflammatory-Type Reaction 3.2. Capecitabine and Its Metabolites 3.3. Enzymes Involved in the Metabolism of Capecitabine 3.4. Transporters Involved in the Absorption of Capecitabine 4. Conclusion Author Information Corresponding Authors Funding Notes Biographies Abbreviations References

© 2016 American Chemical Society

Capecitabine is a novel oral fluoropyrimidine prodrug, which was approved by the U.S. Food and Drug Administration (FDA) in 1998 and has been a frequently chosen ligand to inhibit thymidylate synthase (TYMS).1 Capecitabine has a broad spectrum of anticancer activity and is effective in fluoropyrimidine-sensitive diseases. It is currently being used as an adjuvant therapy of colorectal cancer and a first-line treatment for metastatic colorectal cancer. Capecitabine alone or plus docetaxel combination therapy was used in patients with metastatic breast cancer.2 Clinical studies indicated that capecitabine-based therapy in colorectal cancer showed a 24% response rate.3 In a phase II study, in patients with paclitaxelrefractory metastatic breast cancer, therapy with capecitabine alone can elicit a response rate of 20%.4

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Received: June 16, 2016 Published: September 15, 2016 1591

DOI: 10.1021/acs.chemrestox.6b00215 Chem. Res. Toxicol. 2016, 29, 1591−1601

Chemical Research in Toxicology

Review

Figure 1. Metabolic pathway of capecitabine. Abbreviations: 5′DFCR, 5′-deoxyfluorocytidine; 5′DFUR, 5′-deoxyfluorouridine; 5-FU, 5fluorouridine; 5-FUH2, 5-dihydrofluorouracil; FUPA, α-fluoro-β-ureidopropionate; CES, carboxyleterase; CD, cytidine deaminase; TP, thymidine phosphorylase; UP, uridine phosphorylase; DPD, dihydropyrimidine deshydrogenase; DPYS, dihydropyrimidine.

role in HFS, including the definition and clinical presentation of HFS and the current theories surrounding the mechanism of HFS.

The pharmacokinetic profile of capecitabine is characterized by a rapid and almost complete gastrointestinal tract absorption, followed by three metabolic steps to 5-fluorouracil (5-FU). Capecitabine is initially transformed to 5′-deoxy-5fluorocytidine (5′-DFCR) by carboxylesterase 2 (CES2), then to 5′-deoxy-5-fluorouridine (5′-DFUR) by cytidine deaminase (CD) in carcinoma and in the liver, and to 5-FU by thymidine phosphorylase (TP), which is presented in neoplastic tissue. This results in the release of 5-FU preferentially in the neoplastic tissue.1 Subsequently, 5-FU is transformed by dihydropyrimidine dehydrogenase (DPD) to 5-dihydrofluorouracil (5-FUH2), α-fluoro-β-ureidopropionate (FUPA), and αfluoro-β-alanine (FBAL), which is detected as a urine excretion product. Further activation of 5-FU is likely to occur through ribosylation and sequential phosphorylation in cells.1 Finally, the three intracellularly formed metabolites (nucleotides), viz. 5-fluorouridine 5′-triphosphate (FUTP), 5-fluoro-2′-deoxyuridine 5′-triphosphate (FdUTP), and 5-fluoro-2′-deoxyuridine 5′-monophosphate (FdUMP) (Figure 1), are deemed the antitumor ingredients of capecitabine. Briefly, FUTP can be misincorporated into RNA and disturb RNA biosynthesis and function. FdUTP is misincorporated into DNA, causing DNA strand breaks and cell death. FdUMP is the inhibitor of TYMS, which catalyzes the transformation of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP). This inhibition leads to accumulation of deoxyuridine triphosphate (dUTP) and depletion of deoxythymidine triphosphate (dTTP), which has harmful effects of DNA synthesis and repair, eventually causing cell death. The maximal concentrations of 5′-DFCR, 5′-DFUR, and 5-FU occur between 1 and 2 h following oral administration of capecitabine. Capacetabine and its metabolites are primarily excreted via the kidneys (>95%), with a half-life ranging between 0.5 and 1.3 h.1,5 The FDA recommended dose is 1250 mg/m2 twice a day; however, 1000 mg/m2 is better tolerated.6 Diarrhea, nausea, vomiting, stomatitis, and hand−foot syndrome (HFS) were the most common adverse effects of capecitabine. HFS is a serious dose-limiting toxicity, which can lead to the cessation of therapy or dose reduction.6 In this Review, we focus on capecitabine, a rationally developed oral 5-FU prodrug, with a special emphasis on its

2. DEFINITION AND CLINICAL PRESENTATION OF HAND−FOOT SYNDROME HFS, also called as palmar−plantar erythrodysesthesia, palmar− plantar erythema, acral erythema, and Burgdorf reaction, is a distinctive skin side-effect of chemotherapeutic agents. This syndrome was first described by Dr. Zuehlke in a patient taking mitotane therapy.7 Pathological changes of HFS are vacuolar degeneration of basal keratinocytes, dermal perivascular lymphocytic infiltration, apoptotic keratinocytes, and dermal edema.8 Initial symptoms of HFS are dysesthesia, tingling in the palms, fingers, and soles of the feet, and erythema, which may progress to an extremely painful and debilitating condition without prompt management. The palms of the hands are more frequently affected than the soles of the feet. These symptoms can potentially lead to a worsened quality of life in patients taking capecitabine.9,10 Moreover, the adverse reaction necessitates dose-reduction or withdrawal of the chemotherapeutic agent.11 Furthermore, infectious complications, although uncommon, can lead to significant incidence and trigger a potential life-threatening reaction in rare instances.11,12 Many different systems have been adopted for assessment and classification of HFS. The clinical presentations of HFS are classified into three stages on the basis of the severity and the pathological features. The U.S. National Cancer Institute (NCI)’s three-grade classification system and World Health Organization (WHO)’s four-grade classification criterion are presented in Table 1.13 Capecitabine offers a more selective alternative to 5-FU, as it is converted into the active form specifically in the tumor cells, lowering the adverse effects related to 5-FU, including neutropenia and stomatitis.1 Even so, HFS occurs in a large percentage (almost 50%) of capecitabinetreated patients, with 17% of the patients suffering from a serious form (grade 3).10 1592


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N/A, not applicable.

desquamation, ulcartion, blistering, severe pain N/Aa 4

3+ blister

complete epidermal necrosis

3. POSSIBLE PATHWAYS OF CAPECITABINE-INDUCED HFS 3.1. COX Inflammatory-Type Reaction. Cyclooxygenase (COX) has two isoforms, COX-1 and COX-2. Constitutive expression of COX-1 is found in normal tissues, and it is considered as a housekeeping gene. However, COX-2, a synaptically induced enzyme, plays a crucial role in prostanoid synthesis involved in pain and inflammation. COX-2 can be induced by many inflammatory and mitogenic stimuli.14 Most clinicians believe that HFS is a type of inflammation mediated by COX-2 over-expression in the palm and plantar which may be triggered directly or indirectly by capecitabine or its metabolites.15 Tissues affected by HFS were examined with a microscope, which revealed systemic inflammatory changes with white blood cell infiltration, dilated blood vessels, and edema.9 COX-2 inhibitors have been considered as a general strategy to reduce HFS. Both retrospective and prospective studies have investigated the effect of celecoxib on the occurrenc of capecitabine-related HFS in metastatic colorectal cancer.13,15,16 There is extensive evidence to suggest that the over-expression of COX-2 acts as an independent prognostic marker for tumor stage, size, and modal status. Additionally, chemotherapy can cause over-expression of COX-2. Hence, celecoxib can enhance the antitumor activity of capecitabine via inhibition of COX-2 expression.16 Thus, taken together, selective COX-2 inhibitors can markedly decrease the incidence rate of HFS, and COX-2 plays a crucial role in HFS. However, most clinical trials are characteristically small or single-centered, a fact that could influence the lack of statistical significance. Larger, multicentric studies are required to reinforce this finding.17 3.2. Capecitabine and Its Metabolites. In addition to COX inflammatory-type reaction, other explanations have been posited for the mechanism of HFS associated with capecitabine and its metabolites. It is hypothesized that local trauma could affect the capillaries in the palms and soles, resulting in possible drug extravasation from microcapillaries and its accumulation in the tissues.18 For instance, capecitabine might be secreted by the eccrine sweat glands and directly elicit toxicities. Since the highest number of eccrine glands are present in the palm and plantar, the resulting excretion and accumulation of capecitabine in these areas might lead to HFS.13 In a previously reported study, unilateral HFS in a patient appeared to be related to capecitabine.19 It was hypothesized that the absence of HFS on the right side of the patient’s body could be attributed to right hemiplegia caused by a previous stroke. It was further believed that the hemiplegia might have caused changes in the skin that prevented the accumulation of capecitabine and its metabolites. It is, therefore, conceivable that preventing drug access to the palms and soles will prevent HFS. However, a punch biopsy of skin and the tissue beneath of the right hand of the patient did not show any eccrine abnormalities. The results indicated that vacuolar degeneration was clearly observable in the basal layer of the epidermis, and a mild superficial perivascular lymphocytic infiltrate was shown in the dermis. There were no obvious histopathologic changes observed in the eccrine glands.20 Another theory suggested that HFS results from increased vascularization, pressure, and temperature in the palm and plantar.9,13 The characteristics of the skin on the limbs, including grads of temperature, vascular morphology, rapidly dividing epidermis, and an increased large number of eccrine sweat glands, support the

a

isolated necrotic keratinocytes in higher layer of the epidermis painful erythema and swelling of pains and soles, periungual erythema, and swelling ulcerative dermatitis or skin changes with severe pain interfering with activities of daily living; tissue breakdown is evident (e.g., peeling, blisters, bleeding, edema) 3

discomfort in holding objects and upon walking, painless swelling or erythema skin changes present with accompanying pain interfering little with activities of daily living; skin surface remains intact

2+ fissuration

histological findings

2

1+ edema

erythema

clinical lesion definition

1

dysesthesia/paraesthesia, tingling of hands and feet

definition

minimal skin changes or dermatitis (e.g., erythema, peeling) with altered sensations (e.g., numbness, tingling, burning) but do not interfere with activities of daily living

grade

WHO grade NCI grade

Table 1. NCI and WHO Classifications

dilated blood vessels of the superficial dermal plexus


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3.3. Enzymes Involved in the Metabolism of Capecitabine. The results of a clinical study showed that patients with HFS had higher TP and lower DPD levels in tumors than those without; however, these differences were not significant.28 It has been hypothesized that HFS may be associated with the activity of enzymes responsible for the metabolism of capecitabine, namely TP, UP, or DPD.24,28−30 Mammalian UP and TP are members of the family of nucleoside phosphorylases with related structures.31 A number of studies showed that the expression of TP was higher in various malignant tumors than in the tumor-adjacent normal tissues.32 The activity of UP was reported in various human cells and tissues and was often elevated in solid tumors.33 Previous histological findings from case reports of HFS associated with capecitabine showed hyperkeratosis as well as vacuolar degeneration in the basal layer of the epidermis.20 Keratinocytes express high levels of TP and UP. TP is responsible for capecitabine activation and is markedly expressed in the skin.21,32 One can thus draw the supposition that the capecitabine-induced HFS may be partly due to the increased expression of TP in the skin, especially in the hands and feet. Epidermal renewal is particularly active in these areas, which suggests that cell proliferation is rapid and TP activity is elevated in this cutaneous area.21 The capacity of the proliferative keratinocytes to salvage extracellular thymidine and then to form nucleotides supported this hypothesis.34 In addition, the proliferation rate of the basal keratinocytes of the palm was significantly higher than that of cells in the back, potentially increasing the sensitivity of these cells to cytotoxic drugs.13,35 A study in healthy volunteers (N = 12) also revealed significantly higher levels of TP in the palm as compared to the levels in a control area of the body (the back).24 UP activity plays an important role in the metabolism of 5′-DFUR and 5FU. However, the effect of TP inhibition on drug sensitivity was much more than that caused by UP inhibition. In addition, TP expression was 3−10-fold higher in tumor cells than in surrounding normal tissue cells, which enables selective drug tumor-specific activation of 5-FU and limits systemic toxicity.36 The potent and specific TP inhibitor (thymidine phosphorylase inhibitor, TPI)37 and UP inhibitor (5-benzyacyclouridine, BAU)32 served to regulate the enzyme activities. TdR and Urd phosphorolysis was inhibited by TPI and BAU, respectively, and the two enzymes were involved in the phosphorolysis of 5′-DFUR to 5-FU. 5′-DFUR was rapidly transformed to 5-FU in cells, which led to the increase of the 5FU concentration in the medium. Addition of BAU inhibited the 5-FU production by 20% (p < 0.05), but 5-FU was undetectable in the medium in the presence of TPI.32 Inhibition of both UP and TP did not block the anabolism of 5-FU, since 5-FU can also be metabolized by orotate phosphoribosyltransferase (OPRT). Moreover, TP is an angiogenic marker;38 as a result, this local toxicity may also be related to higher blood flow in the palm. The cytokines TNF-a, IL-1a, and IFN-g enhanced the TP expression in human cancer cell lines.39 Other studies suggested that the upregulation of TP was induced by VPA and other HDACi.40 The elevated expression of TP in the HFS target tissues may support the locoregional toxicity by increasing accumulation of 5-FU during treatment with capecitabine, which could lead to HFS.24 Juneja et al. found no correlation of TP and DPD levels with the morbidity of HFS; however, they suggested a low incidence of HFS in patients receiving capecitabine and radiotherapy (XRT) treatment.13 Additional studies are

notion of capecitabine in eccrine sweat leading to alterations in the skin. One hypothesis is that higher levels of TP are observed in the palm and plantar skin keratinocyte cells, which lead to the generation and accumulation of 5-FU.21 In the in vitro study, the transformation of 5′-DFUR to 5-FU indicated the higher TP activity in HaCaT cells.21 This conversion is essential for its cytotoxicity and could be the cause of 5′-DFUR toxicities, including HFS. This cytotoxic effect of the locally generated 5FU is accentuated by the increased proliferation rate in the palm and sole. This could cause the accumulation of capecitabine metabolite, resulting in an increased possibility of developing HFS. However, pharmacokinetic studies indicated that the 5-FU concentrations in serum were low after treatment with capecitabine; hence, the cause for the high morbidity of HFS induced by capecitabine is unclear.22 Another theory postulates that the metabolites of 5-FU lead to the capecitabine-induced HFS. The indirect evidence to support this hypothesis is that patients who take oral 5-FU prodrugs, including DPD inhibitors like uracil/tegafur (UFT), had low incidence and risk of developing HFS.23 The high expression of Ki67 implied the rapidly proliferation of basal keratinocytes, which make the skin on the palm and sole more sensitivity to the cytotoxicity of the locally produced 5-FU metabolites.24 The theory that 5-FU metabolites may play a role in HFS was supported by the higher plasma concentrations of 5-FUH2 and FBAL than those of 5-FU and 5′-DFUR in the patients receiving capecitabine.5 These metabolites of 5-FU are further transformed and cause DNA strand breaks by incorporation into either the RNA or DNA. Alternatively, these metabolites can inhibit TYMS, leading to a depletion of dTMP. The main metabolites of 5-FU, such as 5-FUH2 and FBAL, were cytotoxic according to previous data. For instance, Diasio et al. reported that the LD50 of 5-FUH2 was 2.7-fold higher than that of 5FU in Ehrlich ascites tumor cells, whereas FBAL did not show a major cytotoxicity.24 However, FBAL showed cytotoxictity on cultured murine cerebellar myelinated fibers.25 Other reports showed that FBAL had no significant cytotoxicity to epithelial cells.26 The combined effect of fluoropyrimidines and metabolites in the plasma of patients receiving capecitabine was investigated by looking at human keratinocytes in culture. HaCaT was selected as a cell model for investigating the connection of HFS to these metabolites. It appears that the IC50 values of 5-FU or 5′-DFUR were several orders of magnitude higher than those of 5-FUH2. The toxicity of 5-FUH2 was 10-fold less than that of 5-FU, and that of FBAL was very limited in HaCaT cells. These results were explained by the retroconvertion of 5-FUH2 to 5-FU by DPD.27 The catabolites, 5-FUH2 and FBAL, showed little direct cytotoxicity on a keratinocyte cell line and did not increase the cytotoxic effect of 5′-DFUR.21 Relative to 5′DFUR and 5-FU, the proportions of FBAL and 5-FUH2 were high in patients treated with capecitabine, which indicated capecitabine favored the production of 5-FU catabolites.5 Remarkably, the addition of other metabolites to 5′-DFUR did not enhance the cytotoxicity of 5′-DFUR.21 However, there is no evident correlation between the plasma concentrations of the capecitabine metabolites 5′-DFUR, 5-FU, and FBAL and the frequency or severity of HFS in the clinical studies. These findings are in good agreement with the results for all grade 3 and 4 adverse events.22 According to historical experience, HFS is dose-dependent and probably related to the accumulation of metabolites of 5-FU in the skin.9 1594



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Additional geno-variations through the CD promoter were also explored. An insertion, rs3215400 which was in a linkage disequilibrium with rs532545, was highly correlated with HFS in patients (OR = 0.51, 95% CI = 0.27−0.95, p = 0.028). The correlation with gene expression was again investigated, and the rs3215400 variant was found to be associated with a significant difference in CD mRNA levels. The deleted allele of rs3215400 in the CD gene suggested an elevated allele-specific gene expression and was clearly correlated with an enhanced risk of capecitabine-related HFS. In particular, carriers of at least one inserted C allele of rs3215400 had a lower risk of developing grade 3 HFS (OR = 0.37, p = 0.020) compared to individuals homozygous for the deleted allele.52 Ribelles and colleagues also analyzed the association between the rs3215400 CD polymorphism and HFS; however, no significant correlation was found.53 Because of the limited sample size in this study, the negative result could be a consequence of a lack of statistical power. No evidence of association was found for the polymorphisms in the other genes considered, such as CES2, TP, DPD, and the target gene (TYMS).52 Martin et al. reported that CES rs11075646 was related with HFS in a randomized Phase II trial comparing two schedules of capecitabine in patients with metastatic breast cancer.54 TYMS is a homodimeric protein consisting of identical subunits and is one of the most conserved protein entities in nature.55 TYMS is the key enzyme in the process of thymidylic acid synthesis and is one of the main targets of the 5-FU and its active metabolite (FdUMP).56 Due to its pivotal role in the folate metabolic pathway, TYMS also serves as an important precursor for the biosynthesis of DNA, RNA, and proteins.57 TYMS catalyzes the de novo synthesis of dTMP, dihydrofolate, and 5,10-methylenetetrahydrofolate (mTHF). Owing to its essential role in the biosynthesis of DNA, TYMS remains a helpful potential target for tumor treatment. TYMS polymorphisms VNTR2R and 3′-UTR 6-bp ins-del were related to the toxic effects of patients treated with capecitabine. The rs2612091 and rs2741171, which were downstream of TYMS and lay within an intron of enolase superfamily member 1 (ENOSF1), were correlated with HFS.49,58 Thus, TYMS may have an influence on the risk of developing HFS. The dUrd is often served as a surrogate marker of TYMS inhibition in patients due to its association with dUMP.59 The observed modulation of TYMS and TP expression prompted the researchers to investigate if, consequently, HDACi (particularly VPA) might enhance the sensitivity of breast cancer cells to fluoropyrimidines such as 5′-DFUR and capecitabine.40 3.4. Transporters Involved in the Absorption of Capecitabine. Although metabolism is necessary to develop the toxicity induced by capecitabine, transporter-medicated transmembrane transport is also required for capecitabine to exert its toxicity. In addition to the enzymes that are responsible for the metabolism of capecitabine, transporters have been posited for the mechanism of HFS associated with capecitabine. 5-FU and its prodrugs, namely capecitabine, require cellular uptake before they can be intracellularly converted to active metabolites that can cause cytotoxicity. Several ABC transporters seem to play a role in fluoropyrimidine-based chemotherapeutic response. This observation is based on in vitro studies using carcinoma cell lines, correlations of ABC transporter expression with resistance in clinical specimens of cancer patients, or pharmacogenetics studies. In the pharmacogenetics studies, the genetic variants of ABC transporter genes have been correlated with the treatment

required to determine whether the expression of enzymes such as TP or DPD plays a part in the mechanism of HFS related to capecitabine. These contrasting results indicated that further work is needed to fully clarify the pathogensis of capecitabinerelated HFS. Pharmacogenomics studies have correlated drug efficacy and toxicity with patient genome variations. Determination of polymorphisms in xenobiotic metabolizing enzymes prior to administration of capecitabine might suggest new strategies for optimizing chemotherapy for individual patients. The relationship between polymorphisms in the DPD, MTHFR, and TYMS genes and both toxicity and efficacy in patients receiving 5-FU or capecitabine has been extensively studied, but the results were often limited and contradictory.41 DPD is widely expressed in tissues and is the rate-limiting enzyme in the catabolic pathway.42−44 It is responsible for more than 80% of the metabolism of 5-FU and capecitabine. DPD mediates a balance between the anabolism and catabolism of 5FU. The number of metabolites generated by the catabolic pathway driven by DPD has also been implicated in the pathogenesis of 5-FU toxicities, including HFS.18 Thus, the elevated expression of DPD in the hand and foot areas should increase the local accumulation of 5-FU catabolites and may enhance cytotoxic effects in this target tissue.24 However, DPD activity was not detected in the keratinocyte cell line.21 Inhibition of DPD renders a direct 5-FU absorption and increasing half-life, which suggested a reduced administration frequency of fluoropyrimidines.45 DPD inhibitors can elevate concentrations of 5-FU and its anabolite and reduce the decomposition of the metabolites of 5-FU.24 Severe 5-FU toxicity may be associated with a genetic deficiency in the activity of the enzyme DPD, which is responsible for the catabolism of 5-FU and capecitabine.42,47,48 Several polymorphisms in the coding region of DPD have been investigated.42,46−48 The intragenic rs12132152, which is 22 kb downstream of DPD, and rs76387818 were strongly associated with HFS.49 Literature also showed that certain ethnicities might be predisposed to decreased DPD enzyme activity.48 For instance, in a study in healthy volunteers (N = 258), DPD deficiency was 3 times more common in African Americans than in Whites (8.0 vs 2.8%, p = 0.07).48 However, this theory fails to explain the safety of capecitabine in patients with DPD deficiency.50 CD found mainly in the liver and neoplastic tissues deaminates 5′-DFCR to 5′-DFUR. The CD gene encodes an enzyme participating in the pyrimidine salvage pathway and irreversibly catalyzes the hydrolytic deamination of cytidine and deoxycytidine to their corresponding uridine derivatives.51 In addition, CD plays a critical role in the metabolism of many antitumor cytosine nucleoside analogues, causing their pharmacological activation to 5-FU. The relationship between grade 3 HFS and genetic variations in the enzymes responsible for metabolism of capecitabine was investigated by Caronia et al. Thirteen polymorphisms in the CES2, CD, TP, TYMS, and DPD genes in 130 patients taking oral capecitabine were genotyped, and the associations of these polymorphisms with the susceptibility to HFS were also studied.52 These findings showed a significant relationship with HFS only for a polymorphism in the CD gene. In particular, the polymorphic T allele of rs532545 was associated with higher incidence of grade 3 HFS; the estimated OR was 2.02 (p = 0.039). There was no correlation between the rs532545 and CD mRNA expression in the Epstein−Barr virus lymphoblastoid cells. 1595



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Table 2. Summary of Possible Pathways of Capecitabine-Induced HFS pathway

study design

COX inflammatory type reaction

clinical clinical clinical clinical

capecitabine and its metabolites

case reports case reports case reports

enzymes involved in the metabolism of capecitabine

study study study study

reference(s) 77 8, 78 15 16 19 20 79, 80

in vitro study clinical study clinical study clinical study clinical study in vitro study in vivo study in vitro study clinical study

excretion and accumulation of capecitabine induced HFS a punch biopsy failed to show any eccrine abnormalities HFS may result from increased vascularization and increased pressure and temperature in the hands and feet higher levels of TP led to the generation and accumulation of 5-FU serum concentrations of 5-FU were low after oral administration of capecitabine HFS is nonexistent in patients who receive uracil/tegafur (UFT) TP facilitated local production of 5-FU in the palm during capecitabine treatment 5-FU metabolites may play a role in HFS 5-FUH2 was cytotoxic, and FBAL did not exhibit a major cytotoxic effect FBAL showed cytotoxic effects 5-FUH2 and FBAL showed little direct cytotoxic effect on a keratinocyte cell line HFS had no correlation with plasma concentrations of various capecitabine metabolites

21 22 23 24 81 27 25, 26 21 82

in vitro study

HFS may be due to the presence of elevated TP activity in the skin

21

clinical study clinical study clinical study

level of TP in the palm was higher than that in a control area of the body (the back) TP and DPD levels had no correlation with the incidence of HFS the higher the DPD expression, the higher was the local production of 5-FU catabolites, and the stronger was the cytotoxicity observed DPD polymorphisms rs12132152 and rs76387818 were strongly associated with HFS CD polymorphism rs3215400 showed a significant association with capecitabine-induced HFS a 5′ untranslated region polymorphism in the CES2 gene was associated with HFS. TYMS polymorphisms rs2612091 and rs2741171 were strongly associated with HFS

24 83 24

clinical study clinical study clinical study clinical study transporters involved in the absorption of capecitabine

investigators’ conclusion COX-2 inhibitor can be used to reduce the frequency of HFS tissues affected by HFS showed general inflammatory changes celecoxib can be used effectively and safely to prevent capecitabine-related HFS celecoxib could prevent capecitabine-related HFS

clinical study in vitro study in vitro study in vitro study in vitro study in vitro study

significant associations were found between moderate to severe HFS and the three ABCB1 SNPs 5-FU may be a specific substrate of BCRP 5-FU was not the substrate of MRP5 metabolites; FUMP, dUMP, and FdUMP were identified as substrates of MRP5 5′-DFUR was an hCNT1 substrate 5-FU was an hOAT2 substrate 5′-DFUR was an hENT1 and hENT2 substrate

outcome and/or occurrence of toxicity.60,61 ATP-binding cassette sub-family B member 1 (ABCB1; also called multidrug-resistance 1 (MDR1) or P-glycoprotein (P-gp)), is a member of the ABC transporter superfamily. ABCB1 has rich polymorphism, with significant differences among different ethnic groups.62,63 The relationship between the ABCB1 polymorphism and the response to 5-FU in colorectal cancer was not clear. However, only a few studies as yet have been concerned with the toxicity, although the truth is that toxicity is always associated with efficacy. In particular, three ABCB1 SNPs, rs1128503 (C1236T), rs2032592 (G2677A/T), and rs1045642 (C3435T), are the most frequently investigated. In patients with moderate to severe HFS, the rates were 30.8, 16.7, and 9.1% for CC, CT, and TT, respectively. Statistical significance of associations was found, indicating a lower occurrence of HFS for the carriers of the T variation for rs1128503 (p = 0.027) and rs1045642 (p = 0.033), respectively, in patients receiving capecitabine.64 The relationship between P-gp (ABCB1) and capecitabine or 5-FU is still unclear. However, other ABC family members, such as ABCC3, ABCC4, ABCC5, and ABCG2, have been shown to transport 5-FU across the membrane.65,66 5-FU was not found to be a substrate

49 52 54 49 64 66 67 70 71 73

of MRP5 (ABCC5); instead, the metabolites FUMP, dUMP, and FdUMP were identified as substrates transported by MRP5 (ABCC5).67 Thus, ABCB1 gene polymorphisms are associated with the adverse effects induced by fluoropyrimidine therapy, which indicated P-gp (ABCB1) might participate in the transport of capecitabine or its metabolite. The members of three families (SLC22, SLC28, and SLC29 families) within the large superfamily of SLC transporters have been associated with the uptake of 5-FU.68 The SLC28 family is also known to transport nucleoside and nucleobase drugs, and the three members CNT1 (SLC28A1), CNT2 (SLC28A2), and CNT3 (SLC28A3) have been found to transport 5′-DFUR as well.69 Particularly, hCNT1 exhibits high affinity for 5′-DFUR, with an apparent Km value of around 200 μM, and the heterologous expression of hCNT1enhances cell sensitivity.70 The organic anion transporter 2 (OAT2, SLC22A7) mediates the uptake of 5-FU with high affinity (Michaelis−Menten constant Km = 54 nM). On the other hand, the two equilibrative nucleoside transporters (ENTs) 1 and 2 (encoded by SLC29A1 and SLC29A2) transport 5-FU with Km values of 2.3 and 2.6 mM, respectively.71,72 ENT1 and ENT2 also transport 5′-DFUR.73 Partial protection of MCF7 cells from 5′1596



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the activities of enzymes and transporters responsible for the metabolism and absorption of capecitabine. It is difficult to determine the exact enzymes or transporters responsible for HFS. The keratinocytes of human skin express various transport proteins and metabolic enzymes. Therefore, they provide the active efflux and uptake capability for biotransformation of a series of xenobiotics, including therapeutic drugs, organic solvents, and pro-carcinogens.84 Xenobiotic-metabolizing enzymes and transports are considered as a second barrier function of the human skin. The major organ involved in drug metabolism is the liver; however, most active metabolites are too reactive to reach the skin in significant concentrations. It is also evident that metabolism within the skin may be an essential step in the manifestation of cutaneous toxicity of certain drugs and chemicals.85 Increasing concentrations of drugs are strongly related to the occurrence of these toxic effects. Accordingly, drugs and metabolites accumulated in the dermal cells can be a decisive factor in drug-related adverse reations in the skin. Drug transporters in the skin may have a vital part in determining the intracellular drug concentrations and metabolites. Capecitabine-induced HFS is a cutaneous reaction in the palm and sole skin. Marked hyperkeratosis was observed with many apoptotic keratinocytes, which indicated that the pathogenesis of HFS was a major toxicicity in the basal keratinocytes. It appears from this scientific evidence that further studies on the enzymes and transporters in the skin could elucidate the exact mechanism of HFS induced by capecitabine. However, the available research has been focused on the toxicity of capecitabine and its metabolites in the keratinocytes, and little attention was paid to their metabolism and transport in the skin. In addition, three identifiable layers comprise the human skin, viz., the epidermis, dermis, and hypodermis. Because of their relative ease operation, HaCaT cell lines have been the most widely used tool to predict the cutaneous toxicity of capecitabine or its metabolites; however, a primary disadvantage is in the absence of 3D tissue properties. 3D culture models were generated from primary human keratinocytes which were grown at the air−liquid interface and allowed to differentiate into a 3D tissue.86 Various epidermal 3D cell models have been developed, including Epi2000, EpiDerm, SkinEthic, and EpiSkin.86,87 Many 2D and 3D human skin culture systems should be used in further studies. Despite the description of the possible mechanism of HFS induced by capecitabine in current studies, much remains to be determined. Several questions need to be addressed, including what chemical substance is involved in inducing HFS, how do capecitabine or its metabolites reach the skin and its target, which transporter mediates this transport, why do different patients develop various reactions to capecitabine, and how do the patients who develop an HFS differ from those who do not. Additional study is needed to determine the function of skin metabolism in the mechanism of HFS. Metabolic studies in the skin relative to the liver had many difficulties, for example, the lack of a faithful animal model, which hampered the progress of research. The results suggest that more work needs to be done to fully clarify the pathophysiological basis for HFS due to capecitabine. Capecitabine is a convenient option for oral chemotherapy; therefore, further research to alleviate HFS is warranted. It is also important to screen patients at high risk for capecitabine-induced HFS in advance of treatment.

DFUR-mediated cytotoxicity through the inhibition of hENT1 by nitrobenzyl thioinosine (NBTI) resulted in a 4-fold increase in the IC50. hENT1 is essential for 5′-DFUR-induced toxic effects, and its deficiency may cause capecitabine resistance. Molina-Arcas et al. have used a concentration of 5′-DFUR close to the IC50 for inhibition of hENT1 (i.e., NBTI was added); under these circumstances, hENT2 is primarily involved in the uptake of 5′-DFUR. However, despite this, most of the 5′DFUR-induced transcriptional changes were blocked by NBTI, which indicated that hENT1, but not hENT2, might play a key role in a general toxic reaction to this drug.74 5′-DFUR is a substrate for hENT1; hence, hENT1-mediated transport appears to be a good possibility for regulating 5′-DFURinduced cytotoxicity. Since hENT1 plays an important in the full transcriptional response to 5′-DFUR therapy, researchers have observed the association between hENT1 expression and response to therapy and clinical outcome, which deduced was from the incipient clinical data.74

4. CONCLUSION HFS is a common toxic effect seen upon treatment with capecitabine. If not promptly managed, HFS can disturb the activities of daily life, especially when moist desquamation, blistering or severe pain, or ulceration occur. The causative mechanisms of HFS are still unclear. As a result, effective strategies to prevent and cure HFS have not yet been established. In the absence of tangible evidence, most expert panels and guidelines recommend dose reduction, or treatment deferral, as key prevention strategies.75 For patients experiencing grade 2 or 3 HFS, treatment interruption is recommended until symptoms resolve to grade 1 or less. For patients experiencing severe HFS, dose reduction should be implemented for subsequent doses of capecitabine.29 In addition to dose reduction and treatment interruption, supportive treatments can help alleviate symptoms. Currently, the main preventive measures of HFS in the clinic include topical ointments, corticosteroids, nicotine path, vitamin E, vitamin B6, COX-2 inhibitors, and henna.20,76 Topical allopurinol, uracil, bepantol, and corticosteroids are newer strategies under investigation for the prevention of HFS, as indicated by the U.S. National Institutes of Health.70 It is essential to understand the possible mechanism of HFS in order to provide effective prevention and treatment measures. In this Review, we have summarized the possible pathways of HFS induced by capecitabine (Table 2). It can be observed that, although several studies have been performed, the exact mechanism of HFS is still unclear, which may be attributable to the fact that current studies are limited to in vitro experiments, clinical cases, and small or single-centered clinical trials. One theory proposed that HFS was due to COX-2mediated inflammation in the hand and foot areas. There is only limited direct evidence to support this hypothesis; hence, it is hoped that this Review will stimulate the search for conclusive evidence and further validation in large-scale clinical trials. It is unknown whether capecitabine or its metabolites directly or indirectly trigger inflammation. Another theory suggests that the accumulation of metabolites in the skin could be responsible for HFS. Interestingly, there is no obvious association between plasma concentrations of the metabolites of capecitabine and the occurrence or severity of HFS. However, toxicity may also be enhanced through the transport of certain drugs by sweat, perhaps facilitated by a hydrophilic coating. It has been hypothesized that HFS may be related to 1597



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AUTHOR INFORMATION

thymidine triphosphate; NCI, U.S. National Cancer Institute; WHO, World Health Organization; COX-2, cyclooxygenase 2; UFT, uracil/tegafur; TPI, thymidine phosphorylase inhibitor; BAU, 5-benzylacyclouridine; OPRT, orotate phosphoribosyltransferase; XRT, capecitabine/radiotherapy; mTHF, 5,10methylenetetrahydrofolate; ENOSF1, enolase superfamily member 1; ABCB1, ATP-binding cassette B1; MDR1, multidrug-resistance 1; P-gp, P-glycoprotein; OAT2, organic anion transporter 2; ENT, equilibrative nucleoside transporters; 5′DFCR, 5′-deoxyfluorocytidine; UP, uridine phosphorylase; DPYS, dihydropyrimidinase; NBTI, nitrobenzylthioinosine

Corresponding Authors

*Tel.: +86 571 87236675. Fax: +86 571 87236675. E-mail: [email protected]. *E-mail: [email protected]. Funding

This article was supported by the Natural Natural Science Foundation of China (no. 81573502) and Zhejiang Provincial Natural Science Foundation of China (no. LY15H310004). Notes

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The authors declare no competing financial interest. Biographies

REFERENCES

(1) Queckenberg, C., Erlinghagen, V., Baken, B. C., Van Os, S. H., Wargenau, M., Kubeš, V., Peroutka, R., Novotný, V., and Fuhr, U. (2015) Pharmacokinetics and pharmacogeneticsof capecitabine and its metabolites following replicate administration of two 500 mg tablet formulations. Cancer Chemother. Pharmacol. 76, 1081−1091. (2) Figueiredo, A. G., Jr., and Forones, N. M. (2014) Study on adherence to capecitabine among patients with colorectal cancer and metastatic breast cancer. Arq. Gastroenterol. 51, 186−191. (3) Hoff, P. M., Ansari, R., Batist, G., Cox, J., Kocha, W., Kuperminc, M., Maroun, J., Walde, D., Weaver, C., Harrison, E., Burger, H. U., Osterwalder, B., Wong, A. O., and Wong, R. (2001) Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: results of a randomized phase III study. J. Clin. Oncol. 19, 2282−2292. (4) Kamal, A. H., Camacho, F., Anderson, R., Wei, W., Balkrishnan, R., and Kimmick, G. (2012) Similar survival with single-agent capecitabine or taxaneinfirst-line therapy for metastatic breast cancer. Breast Cancer Res. Treat. 134, 371−378. (5) Reigner, B., Blesch, K., and Weidekamm, E. (2001) Clinical pharmacokinetics of capecitabine. Clin. Pharmacokinet. 40, 85−104. (6) Bajetta, E., Procopio, G., Celio, L., Gattinoni, L., Della Torre, S., Mariani, L., Catena, L., Ricotta, R., Longarini, R., Zilembo, N., and Buzzoni, R. (2005) Safety and efficacy of two different doses of capecitabine in the treatment of advanced breast cancer in older women. J. Clin. Oncol. 23, 2155−2161. (7) Zuehlke, R. (2004) Erythematous eruption of the palms and soles associated with mitotane therapy. Dermatology 148, 90−92. (8) Nagore, E., Insa, A., and Sanmartin, O. (2000) Antineoplastic therapy-induced palmar plantar erythrodysesthesia (″hand-foot″) syndrome. Incidence, recognition and management. Am. J. Clin. Dermatol. 1, 225−234. (9) Lassere, Y., and Hoff, P. (2004) Managment of hand foot syndrome in patient treated with capecitabine (Xeloda). Eur. J. Oncol. Nurs. 8, S31−S40. (10) Heo, Y. S., Chang, H. M., Kim, T. W., Ryu, M. H., Ahn, J. H., Kim, S. B., Lee, J. S., Kim, W. K., Cho, H. K., and Kang, Y. K. (2004) Hand−foot syndrome in patients treated with capecitabine-containing combination chemotherapy. J. Clin. Pharmacol. 44, 1166−1172. (11) Takeda, K., Shigematsu, T., Shirai, M., Yamagiwa, K., Amamori, K., Sunda, K., and Yamanda, T. (2012) Assessment of hand-foot syndrome in cancer outpatients undergoing chemotherapy. Gan. To. Kagaku Ryoho. 39, 74−76. (12) Hoesly, J. F., Baker, S. G., Gunawardane, N. D., and Cotliar, J. A. (2011) Capecitabine-induced hand-foot syndrome complicated by pseudomonal superinfection resulting in bacterial sepsis and death: case report and review of the literature. Arch. Dermatol. 147, 1418− 1423. (13) Gressett, S. M., Stanford, B. L., and Hardwicke, B. F. (2006) Management of hand-foot syndrome induced by capecitabine. J. Oncol. Pharm. Pract. 12, 131−141. (14) Harris, R. E. (2007) Cyclooxygenase-2 (cox-2) and the inflammogenesis of cancer. Subcell. Biochem. 42, 93−126. (15) Zhang, R. X., Wu, X. J., Wan, D. S., Lu, Z. H., Kong, L. H., Pan, Z. Z., and Chen, G. (2012) Celecoxib can prevent capecitabine-related hand-foot syndrome in stage II and III colorectal cancer patients:

Yan Lou is a clinical pharmacist in the First Affiliated Hospital of Zhejiang University. She was a postdoctoral fellow at Zhejiang University from 2009 to 2011, and earned her doctorate in pharmacy in 2009. Her research currently focuses on the mechanism of hand− foot syndrome induced by anticancer drugs as well as the drugmetabolizing enzymes and drug transporters. Qian Wang is a student in toxicology at Zhejiang University. Her research currently focuses on the mechanisms of hand−foot syndrome induced by capecitabine. Jinqi Zheng is a researcher at Zhejiang Institute for Food and Drug Control. He earned his Master’s degree in pharmacy from Shenyang Pharmaceutical University in 2004. His research currently focuses on the chemical material basis of capecitabine and its toxicity. Haihong Hu is a Ph.D. candidate in pharmacy at Zhejiang University. Her research currently focuses on molecular mechanisms of drug toxicity. Lin Liu is a clinical pharmacist in the First Affiliated Hospital of Zhejiang University. She is a Ph.D. candidate in pharmacy at Zhejiang University. Her research currently focuses on the correlation between gene polymorphisms and drug-induced hand−foot syndrome among patients with metastatic breast cancer. Dongsheng Hong is a clinical pharmacist in the First Affiliated Hospital of Zhejiang University. He earned his Master’s degree in pharmacy from Zhejiang University. His research currently focuses on skin toxicity and drug metabolism in the skin. Su Zeng is a professor in Laboratory of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University. He obtained his MSc and Ph.D. from the same university. He was the Winner of National Outstanding Youth Science Foundation of China. His main research interests are drug metabolizing enzymes and drug transporters. He is also interested in chiral drug analysis and stereoselective metabolism, drug metabolism in the skin, and toxicity of the anticancer drugs.

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ABBREVIATIONS HFS, hand−foot syndrome; FDA, U.S. Food and Drug Administration; TYMS, thymidylate synthase; 5-FU, 5-fluorouracil; CES2, carboxylesterase 2; 5′-DFUR, 5′-deoxy-5-fluorouridine; CD, cytidine deaminase; TP, thymidine phosphorylase; DPD, dihydropyrimidine dehydrogenase; 5-FUH2, 5-dihydrofluorouracil; FUPA, α-fluoro-β-ureidopropionate; FBAL, αfluoro-β-alanine; FUTP, 5-fluorouridine 5′-triphosphate; FdUTP, 5-fluoro-2′-deoxyuridine 5′-triphosphate; FdUMP, 5fluoro-2′-deoxyuridine 5′-monophosphate; dUMP, deoxyuridine monophosphate; dTMP, deoxythymidine monophosphate; dUTP, deoxyuridine triphosphate; dTTP, deoxy1598



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