手足综合征机制及防治
手足综合症
手足综合症
手足综合症是一种罕见的遗传性疾病，主要影响中枢神经系统的发育，导致患
者在生长和认知方面出现一系列问题。
这种疾病通常在婴儿期或幼儿期被诊断出来，患者在生命的早期阶段便开始表现症状。
患有手足综合症的个体往往显示出不同程度的智力发育迟缓，可能伴随有进行
性肌张力失常和特定表征的面容特征。
这些症状可能表现为肌肉痉挛、大小不均匀的双眼瞳孔、肢体畸形等。
由于这些表现的多样性，手足综合症的确诊往往需要详细的临床检查和基因检测。
虽然手足综合症目前还没有特效的治疗方法，但患者可以通过康复训练和药物
治疗来缓解症状并提高生活质量。
早期干预和综合治疗至关重要，可以帮助患者最大限度地发挥潜力并减轻症状的严重程度。
此外，家庭支持和良好的医疗团队合作对于患有手足综合症的个体也至关重要。
对于那些患有手足综合症的家庭来说，理解和尊重病情、提供良好的心理支持
以及积极寻求医疗帮助是至关重要的。
通过全面的治疗计划和团队的努力，患者可以更好地适应疾病，展现出自己独特的魅力和潜力。
综上所述，手足综合症虽然是一种罕见的遗传性疾病，但通过早期的发现和综
合治疗，患者仍然有机会获得更好的生活质量。
医疗专家、家庭成员和社会各界应共同努力，为那些受该病影响的个体提供更好的支持和关心。
手足综合征
RESEARCH ARTICLEPathogenesis of Hand-Foot Syndrome induced by PEG-modified liposomal DoxorubicinNoriyuki Yokomichi •Teruaki Nagasawa •Ariella Coler-Reilly •Hiroyuki Suzuki •Yoshiki Kubota •Ryosuke Yoshioka •Akiko Tozawa •Nao Suzuki •Yoko YamaguchiReceived:5November 2012/Accepted:11December 2012/Published online:6February 2013ÓThe Author(s)2013.This article is published with open access at Abstract PEGL-DOX is an excellent treatment for recurrent ovarian cancer that rarely causes side-effects like cardiotoxicity or hair loss,but frequently results in Hand-Foot Syndrome (HFS).In severe cases,it can become necessary to reduce the PEGL-DOX concentration or the duration of the drug therapy,sometimes making it difficult to continue treatment.In this study,we prepared an animal model to compare the effects of DOX versus PEGL-DOX,and we noticed that only treatment with PEGL-DOX resulted in HFS,which led us to conclude that extravasa-tion due to long-term circulation was one of the causes of HFS.In addition,we were able to show that the primary factor leading to the skin-specific outbreaks in the extremities was the appearance of reactive oxygen species (ROS)due to interactions between DOX and the metallic Cu(II)ions abundant in skin tissue.ROS directly disturb the surrounding tissue and simultaneously induce kerati-nocyte-specific apoptosis.Keratinocytes express the ther-moreceptor TRPM2,which is thought to be able to detect ROS and stimulate the release of chemokines (IL-8,GRO,Fractalkine),which induce directed chemotaxis in neutro-phils and other blood cells.Those cells and the keratino-cytes then undergo apoptosis and simultaneously release IL-1b ,IL-1a ,and IL-6,which brings about an inflamma-tory state.In the future,we plan to develop preventative as well as therapeutic treatments by trapping the ROS.Keywords Hand-Foot Syndrome (HFS)ÁPalmar-plantar erythrodysesthesia (PPE)ÁPegylated liposomaldoxorubicin ÁDrug delivery system (DDS)ÁReactive oxygen species (ROS)IntroductionStandard cancer treatments currently include surgery,radiation therapy,and chemotherapies such as anticancer drugs;however,there are advantages and disadvantages to each treatment.The specific course of treatment is chosen based on the cancer’s rate of progression,but in most cases,the standard of care is to choose a chemotherapeutic anti-cancer drug.Hair loss,pancytopenia,and nausea/vomiting are the side-effects most typically seen with anticancer drug treatment,but there have also been serious adverse reactions in the skin.These reactions cause intense pain in the hands and feet,and the phenomenon is known as Hand-Foot Syndrome (HFS)or Palmar-Plantar Erythrodysesthe-sia (PPE)[1].In cases where HFS is severe,patients experience difficulty walking and lose the ability to hold objects in the hands,everyday life becomes significantly impaired,and it may become difficult to continue the cancer treatment.Anticancer drugs that have been found to frequently cause outbreaks of HFS include:fluoropyrimidines like capecitabine,which is used to treat colorectal cancer andN.Yokomichi (&)ÁA.Tozawa ÁN.SuzukiDepartment of Obstetrics and Gynecology,St.Marianna University School of Medicine,2-16-1Sugao,Miyamae,Kawasaki,Kanagawa 216-8511,Japan e-mail:n.yokomichi@ n.yokomichi@marianna-u.ac.jpT.Nagasawa ÁH.Suzuki ÁY.Kubota ÁR.Yoshioka ÁY.YamaguchiNANOEGG ÒResearch Laboratories Inc,2-16-1Sugao,Miyamae,Kawasaki,Kanagawa 216-8512,Japan A.Coler-Reilly ÁY.YamaguchiInstitute of Medical Science,St.Marianna University School of Medicine,2-16-1Sugao,Miyamae,Kawasaki,Kanagawa 216-8512,JapanHuman Cell (2013)26:8–18DOI 10.1007/s13577-012-0057-0breast cancer;anthracycline,which is used against malig-nant solid tumors;a PEG-modified liposomal doxorubicin formulation(PEGL-DOX),which is used against recurrent ovarian cancer[2];docetaxel,which is used against a wide variety of cancers;and sorafenib or sunitinib,which are molecular target drugs used against kidney cancer.The frequencies with which certain drugs can induce HFS are ranked as follows:PEGL-DOX as the highest at approxi-mately78%,next is capecitabine at51–78%,andfinally sorafenib at about55%[3].Anticancer drugs are made to cause cellular malfunctions, but the particular reasons for the occurrence of side effects like pain in the hands and feet,reddening and cracking of the skin,numbness,and erythema(red spots)are not understood in much detail.For that reason,there are currently no effective treatments,and the standard practice is to recom-mend moisturizer,or topical steroids in severe cases.PEGL-DOX is exceedingly effective in treating recurrent ovarian cancer without causing side effects like cardiotox-icity,neutropenia,anemia,alopecia,or nausea/vomiting. However,because of the frequency with which HFS occurs, there is a high risk that the patient’s quality of life will severely decline.With regards to insuring the completion of medical treatment,it is extremely important to establish precautionary measures.Therefore,in order to elucidate the mechanism of HFS outbreaks,we carried out in vivo experiments to analyze skin histology in the extremities, cytokine analyses,and in vitro experiments in skin cells. Materials and methodsChemicalsDoxorubicin(DOX,generic for Adriamycin)was obtained from Nippon Kayaku(Tokyo,Japan).In order to make PEGL-DOX(trade name DoxilÒ),a PEG-modified lipo-somal formulation of DOX,lecithin and polyoxyethyle-nated lecithin were obtained from NOF(Tokyo,Japan). Methanol,chloroform,copper chloride,and Mayer’s Hematoxylin and Eosin were purchased from Wako Pure Chemical Industries(Osaka,Japan).Fluorescein sodium salt was purchased for thefluorescent dye experiments from Sigma-Aldrich(St.Louis,MO,USA).DeadEnd TM Fluorometric TUNEL System was purchased for TUNEL staining from Promega(Madison,WI,USA).AnimalsSix-week-old female SD rats and hairless rats were pur-chased from Japan SLC(Shizuoka,Japan),and were used for experiments after1week of rest.The rats were raised in independent cages in50–60%humidity,23±1°C environment with light from0630to1830hours(12-h light–dark cycle)and were given ad libitum access to food and water.All animal experiments were carried out in accordance with the Guidelines for Animal Experimenta-tion of St.Marianna University School of Medicine.Cell cultureFrom in vitro experiment,pathogenesis of HFS was expected to be a leakage of doxorubicin from peripheral vascular in the dermal layer in skin.As it was assumed that the cell in skin should be directly affected by doxorubicin alone,all in vitro experiments have been performed with doxorubicin alone.HaCaT cell lines derived from human keratinocytes were received from Dr.Masamitsu Ichihashi of the Kobe University Graduate School of Medicine,Department of Dermatology.Normal Human Dermal Fibroblasts(NHDF cells)were purchased from KURABO Industries.HaCaT were cultured using Dulbecco’s Modified Eagle Medium (DMEM;Life Technologies,Carlsbad,CA,USA),and NHDF were cultured using DMEM supplemented with GlutaMAX TM Supplement I(Life Technologies,Carlsbad, CA,USA).The media were supplemented with10%fetal bovine serum,100U of penicillin,and100U of strepto-mycin.The cells were cultured at5%CO2and37°C.Preparation of the PEGL-DOXPEGL-DOX was produced from raw materials in the lab-oratory according to the Sadzuka method[4],but the steps involvingfiltration to equalize the particle sizes and the subsequent confirmation of the average particle size were omitted.L-a-distearoylphosphatidyl-DL-glycerol(DSPG,a PEG-modified lecithin)and lecithin were dissolved in a1:4 methanol:chloroform solution and formed a thinfilm on the surface of theflask after the solvent was removed using a rotary evaporator in a35°C hot water bath.Aqueous DOX solution and sorbitol/lactic-acid solution was then added to theflask,and it was stirred for15min in a60°C hot water bath.After3min of sonication,thefinal product was a 0.2%weight/volume PEGL-DOX solution.Physico-chemical properties of PEGL-DOX were confirmed the following methods:(1)observation of aflow birefringence under a polarizing plate,and(2)semi-transparent without turbidity because of emulsified turbid appearance of lipo-some without modified PEG.Preparation of the HFS animal modelsIn order to determine whether the liposome formulation of doxorubicin developed from HFS onset,we have carried out comparative experiments with doxorubicin alone.ToPathogenesis of Hand-Foot Syndrome9prepare the HFS animal models,PEGL-DOX and/or DOX (at10and5mg/kg,respectively)was administered to SD rats via the tail veins once every3days for10days.The limbs were visually inspected and photographed10days later.Afterwards,skin tissue samples from the hind limbs were collected,fixed in formalin,and embedded in paraf-fin.In non-clinical studies reported by dealers in DOXILÒ, they did notfind onset HFS for each additive of the PEGL-DOX preparation.Thus,in the present study,administra-tion of the experiment in vivo was not performed for each additive to confirm the onset of HFS.Tissue StainingThe formalin-fixed paraffin-embedded skin tissue was sliced into4l m sections,deparaffinized,rehydrated,H&E stained,and then observed under an optical microscope. Picrosirius Red staining was applied in order to observe the state of the dermal collagenfibers and visualized under a polarized light microscope.TUNEL staining with the DeadEnd TM Fluorometric TUNEL System was used to detect apoptosis and visualized under afluorescence microscope(BIOZERO;KEYENCE,Osaka,Japan). Measurement of cytokine expression in vivoand in vitroInflammatory cytokines and chemokines were measured in order to investigate the origins of HFS.After the application of the PEGL-DOX treatment,the hind-leg skin tissue was collected and used to measure in vivo expression levels.First the tissue was homogenized,then the samples were centri-fuged,andfinally the supernatant was analyzed using the Rat Cytokine Antibody Array(RayBiotech,North Metro-Atlanta, GA,USA).In addition,in vitro experiments were conducted in order to clarify the influence of DOX on skin cells,spe-cifically epithelial cells.HaCaT cells were cultured in media supplemented with DOX and CuCl2,and the inflammatory cytokines were measured using the Human Cytokine Anti-body Array(RayBiotech).IL-8,GRO,and Fractalkine che-mokines of the CXC family,which corresponds to the CINC3 rat chemokine family were quantified using the Luminex200 system(Millipore,Billerica,MA,USA).Similar experiments were also carried out using NHDF.Creation of a visualizable model of a PEG-modified liposomal drug usingfluoresceinIn order to investigate the phenomenon by which HFS develops selectively in the limbs rather than throughout the whole body,fluorescein(FS)was used to create an easily visualizable model of a PEG-modified liposomal drug.The PEG-modified liposomalfluorescein(PEGL-FS)drug was prepared exactly as the PEGL-DOX drug was prepared.FS or PEGL-FS was administered to hairless rats via the tail vein,and whole-body FS was visualized under a long-wavelength ultraviolet lamp(UVGL-58Handheld UV Lamp;UVP,Upland,CA,USA).Observations commenced immediately after drug administration,and photographs were taken periodically.Skin samples were collected from the soles of the hind-paws at1,7,and24h after drug administration.The OCT compound-embedded tissue was cut into10-l m frozen sections and observed under afluo-rescence microscope.Measurement of DOX toxicity in vitroHaCaT and NHDF cell cultures were used to evaluate the toxicity of DOX in vivo.DOX was added at various con-centrations(0.1–10l M)to the media,and the percentage of viable cells was measured24h later using Cell Counting Kit-8(CCK8;Dojindo Laboratories,Kumamoto,Japan). Results showed that1.5l M exhibited a moderate level of toxicity that was appropriate for the toxicity tests to follow (Fig.1).To test the toxicity in the presence of copper ions, various concentrations of copper chloride(50or375l M) were added to1.5l M DOX media.After24h of culturing, the survival rate was again measured using CCK8.Finally, to test the degree of inhibition of ROS by SODs,100l g/ml SOD(Sigma-Aldrich)was added to the medium,and12h later the survival rate was again measured.Statistical analysisDunnett’s and Tukey’s multiple comparison tests were used to analyze the results of in vitro experiments.The software used was R v.2.15.1[5].Fig.1Survival rate of human skin cells following DOX treatments. HaCaT and NHDF cells were cultured with DOX for24h before counting.The values are presented as mean±SD(n=3).Signif-icantly different from control:*p\0.05,**p\0.0110N.Yokomichi et al.ResultsInjections of PEGL-DOX yielded an HFS-like disease stateSingle or multiple doses of high-dose (10mg/kg)or low-dose (5mg/kg)DOX or PEGL-DOX were administered intravenously to SD female rats,whose limbs were then observed for signs of inflammation or redness.Changes in appearance were compared within single-dose or multiple-dose groups (Fig.2a,b).Within the single-dose group,immediately following PEGL-DOX administration,reddening was observed in the forepaws,hind-paws,ears,and at the tip of the nose;however,no such change was observed after DOX administration even after high-dose treatment (Fig.2a).The redness that appeared was transient and disappeared after 5–10min.Since the thickness of the rat limb skin is very thin,we can normally see the blood vessel through the skin.Because PEGL-DOX has a red color,observed tran-sient redness after injection would correspond to the nat-ural color of PEGL-DOX.Within the multiple-dose group,inflammation was observed after multiple low-dose PEGL-DOX treatments,and the change was even more striking after high-dose treatments (Fig.2b).This observed state of inflammation,swelling,and dryness was judged to be similar enough to human HFS to conclude that HFS had indeed broken out in these rat limbs [6].Skin tissue staining revealed multiple adverse affects of high-dose PEGL-DOXH&E staining clearly revealed the following effects of multiple doses of high-dose PEGL-DOX as compared to an untreated control group:a thinned or even absent granular layer,a decrease in the number of cells between the basal layer and the stratum spinosum,a rougher arrangement of cells,and a thinning of the epithelial layer (Fig.3a).On the other hand,the dermal fibroblasts appeared relatively unaffected.Picrosirius red staining,which stains collagen fibers,revealed disarranged and broken collagen fibers in the multiple-dose PEGL-DOX group (Fig.3b).TUNEL staining,which is a marker for apoptosis,showed that apoptosis was induced in basal epidermal cells in the PEGL-DOX group (Fig.3c).In other words,the results of the TUNEL staining imply that HFS is related to apoptosis induced in epidermal cells.Antibody array showed increased expression of chemokines and inflammatory cytokinesThe proteins expressed in the regions of the rat skin tissue affected by the PEGL-DOX treatment were measured using an antibody array.Markedly increased expression of mul-tiple proteins was confirmed:the chemokines CINC3and Fractalkine,the IL-family-inhibitory IL-10,and inflam-matory cytokines such as IL-1b and IL-6(Fig.4).PEGL-FS yielded more persistent fluorescence than unaltered FS in rat pawsImmediately following administration of PEGL-FS or FS (unaltered fluorescein),very strong fluorescence was observed in the extremities.This fluorescenceweakenedFig.2Rat paws (SD,female,7weeks)after intravenous injection of DOX or PEGL-DOX.a Appearance immediately after 10mg/kg injection.b Appearance after multiple doses.Doses were adminis-tered once every 3days,and photos were taken on the 10th day.Blue circles indicate particularly inflamed areasPathogenesis of Hand-Foot Syndrome 11over time but remained strong in the paws even after 3h,and a small amount of fluorescence remained after 7h in the PEGL-FS group (Fig.5a).Tissue sections at 1h after treatment with either PEGL-FS or FS exhibited fluorescence over the entire dermal layer,indicating a high level of FS retention.It is assumed that the FS leaked out of the capillaries in the dermal layer (Fig.5b).At this point,the PEGL-FS had already started to spread to the epidermis and exhibit fluorescence there.In sections at 7h after treatment,the fluorescence had become concentrated at the upper stratum corneum,which suggested that the fluorescent dye had diffused from the dermis through the epithelium and arrived at the stratum corneum.In the PEGL-FS group,in contrast to theFSFig.3Tissue staining in rat (SD,female,7weeks)paw skin after 10mg/kg PEGL-DOX injection.a H&E staining.Epidermal layer was thinned with respect to control (epidermal layer is shown in blue between the pink stratum corneum and lighter blue dermal layer).b Picrosirius red staining.Color of stain in order of decreasingstrength and thickness of fibers:red ,yellow ,green .PEGL-DOX group displayed disarranged and broken collagen fibers.c TUNEL staining.Red marks nuclei,green marks apoptosis.Only basal cells show signs of apoptosis.(a –c )scale bar 50l m12N.Yokomichi et al.group,a small but noticeable amount of fluorescence remained in the dermis.In addition,the concentration of fluorescence in the stratum corneum appeared slightly higher in the PEGL-FS group than the FS group.DOX and Cu(II)ions increased productionof chemokines and cytokines and lowered cell survival rates,which were rescued by SODIn the regions of the rat skin tissue affected by the PEGL-DOX treatment were measured using an antibody-array,markedly increased expression of multiple cytokines was confirmed:the chemokines CINC3and Fractalkine,the IL-family-inhibitory IL-10,and inflammatory cytokines such as IL-1b and IL-6(Fig.4).Therefore,we studied this mechanism in detail in vitro.HaCaT and NHDF cells were treated with various concentrations of DOX (0.1–10l M)and survival rates were determined after 24h.Results showed that 1.5l M exhibited a moderate level of toxicity that was appropriate for toxicity tests to follow (Fig.1).The presence of the 1.5l M DOX did not detectably increase the production of chemokines in the HaCaT cells,but the addition of Cu(II)ions caused increased production of the aforementioned CXC chemokines GRO and IL-8,with the production volume dependent on the Cu(II)ion concentration (Fig.6a).However,in the NHDF cells,neither DOX alone nor the combination of DOX and Cu(II)ions yielded increased production of chemokines;in fact,DOX appeared to inhibit chemokine production.The effects of DOX and Cu(II)ions on inflammatory cytokine production varied across different cytokines and different cell types (Fig.6b).HaCaT cells produced IL-1a and IL-6in response to the presence of DOX,and pro-duction was further amplified by the addition of Cu(II)ions.The production of IL-1b rose in the presence of DOXcombined with a very high concentration of Cu(II)ions.By contrast,NHDF cells exhibited no noticeable response to DOX alone,and the addition of Cu(II)ions stimulated an increase in only IL-b production.Without the addition of DOX,the survival rate of Ha-CaT cells remained relatively constant across varying concentrations of Cu(II)ions (Fig.7).However,in the presence of DOX,the survival rate of the cells rapidly decreased with increasing Cu(II)ion concentration.By contrast,the NDHF cells were relatively unaffected by the combination of DOX and Cu(II)ions.The addition of superoxide dismutase (SOD)improved this HaCaT cell survival (Fig.8).DiscussionA variety of research has been conducted on the relation-ship between Doxil Ò(trade name for PEGL-DOX)and HFS,and many important discoveries have already been made.Charrois et al.[7]have analyzed the pharmacoki-netics of DOX in rat skin tissue and tumors after multiple doses of Doxil Ò,and results have shown that the half-life of Doxil Òis particularly long in the paws.It has become known that multiple doses of anticancer drugs,or possibly a single large dose,can cause an accumulation of cell damage and a speeding up of the cell cycle in keratino-cytes,which can ultimately lead to an outbreak of HFS [8].By using the skin of humans to whom fluorescence-tagged Doxil Òhad been administered,Martschick et al.[9]have discovered that Doxil Òleaks out from the body in the sweat.Both in vivo experiments in mice and rats and in vitro experiments in HaCaT cells led to the conclusion that DOX toxicity in the skin causes hair-loss via dena-turation of the sebaceous line [10].In addition,the ideathatFig.4Rat Cytokine Antibody Array.Skin tissue from HFS-affected areas after multiple 10mg/kg PEGL-DOX injections.Results werenormalized to controls.Graph shows increased production of chemokines with respect to control.The values are presented as mean ±S.DPathogenesis of Hand-Foot Syndrome 13Manganese SOD (MnSOD)can suppress apoptosis was introduced in an experiment investigating DOX-induced apoptosis in HaCaT cells [11].Finally,it has been reported that the coexistence of DOX and Cu(II)generates ROS,which inflict oxidative damage on DNA [12].As described above,while research on DOX,Doxil Ò,and the skin is plentiful,little is known about why Doxil Ò/PEGL-DOX frequently causes HFS or why the outbreaks occur in the skin tissue.Moreover,there have been no reports of effective treatments for thiscondition.Fig.5Comparison ofphotographs after intravenous injection of 36mg/kg 1.5ml PEGL-FS or FS in hairless rats (female,7weeks).a Photos cropped from whole-body visualization under long-wavelength UV lampimmediately after,3and 7h after injection.PEGL-FS remained fluorescing in the paws 7h post-injection.b Tissue sections cut 1h and 7h after injection.PEGL-FS diffused faster from the dermis through the epidermis to the stratum corneum,lingered in the dermis longer,and showedslightly higher fluorescence than FS.Scale bar (b )100l m14N.Yokomichi et al.The tendency of PEGL-DOX to induce HFS outbreaks in rats where DOX did not led us to the theory that the dif-ference in metabolic stability between the two drugs was the cause of the difference in frequency of HFS outbreaks in humans.In other words,the key difference is that the higher metabolic stability of PEGL-DOX allows it to remain active in the blood for a longer period of time,as illustrated by the presence of PEGL-FS remaining in the rat extremities after 7h (Fig.4).This also means an increase in the frequency with which the drug reaches the hands andfeet.Fig.6Changes in chemokine and cytokine production in HaCaT and NHDF cells following addition of DOX or DOX ?Cu(II)ions to culture medium.a Production of chemokines IL-8,GRO,and Fractalkine (ng/ml).HaCaT cells exhibited DOX-and Cu(II)-dependent production of IL-8and GRO.The values are presented as mean ±SD (n =3).Significantly different from control:*p \0.05,p \0.01.b Production of cytokines IL-1a ,IL-1b ,and IL-6(ng/ml).HaCaT cells exhibited DOX/Cu(II)-dependent increased production of all cytokines shown,and NHDF cells exhibited substantially increased production of IL-1bonlyFig.7Survival rate of human cells in the presence or absence of 1.5l M DOX and varying concentrations of Cu(II)ions.a HaCaT cells.Survival rate declined with increasing Cu(II)ion concentration in the presence of DOX.b NHDF cells showed relatively littleresponse to DOX and Cu(II)ions.The values are presented as mean ±SD (n =3).Significantly different from control:*p \0.05,**p \0.01Pathogenesis of Hand-Foot Syndrome 15In fact,the capillaries are concentrated at the fingertips and the soles of the feet,where the blood flow is high.Unlike three-layer artery or arteriole walls,capillary walls are composed of only a single layer of endothelial cells,which makes capillary walls easy to penetrate with only slight provocation.The capillaries are especially concen-trated in the dermis,which suggests that anticancer drugs might easily leak into the dermis and linger there at high concentrations,as indicated by the results of the experi-ment using the fluorescein drug model PEGL-FS (Fig.4).Doxorubicin is known as the most dangerous of all ves-icant drugs,which are high-risk drugs capable of causing tissue necrosis upon extravasation [13].Therefore,the accumulation of DOX in this tissue is extremely cytotoxic.Many anticancer drugs cause DNA damage in order to induce apoptosis in cancer cells.There have been many experiments that show that apoptosis can be induced by ROS generated directly or indirectly by anticancer drugs [14–18].It is said that DOX damages DNA by generating ROS and inhibiting Topoisomerase II [12].Furthermore,it has been reported that the oxidative damage due to ROS was magnified in the presence of Cu(II)ions in experiments using the human promyelocytic leukemia cells [19].Our own results corroborated the pre-existing evidence that DOX induces apoptosis in keratinocytes via ROS in the presence of Cu(II)ions and that SOD rescues the cells from apoptosis by capturing the ROS in the culture medium [11,20].The effects of DOX and Cu(II)ions on cell viability and chemokine production appear to be tightly correlated.The results of our rat tissue staining experiments (Fig.2)indicate that DOX induces apoptosis in keratinocytes,but not in dermal fibroblasts.Similarly,the results of ourcytotoxicity tests (Fig.7)indicate that,while DOX does not affect fibroblasts,it appears to kill keratinocytes,and it appears to kill at a greater rate in the presence of Cu(II)ions.As for chemokines,the pattern is similar.While fibroblasts do not appear to produce chemokines even in the presence of both DOX and Cu(II)ions,keratinocytes produce the chemokines IL-8,GRO,and Fractalkine in response to DOX,and IL-8and GRO are produced in a Cu(II)concentration-dependent manner (Fig.6).The fact that chemokine production spiked in areas of rat skin tissue afflicted with HFS (Fig.3)suggests that these chemokines represent an important part of the mechanism by which injection of PEGL-DOX leads to HFS.Yamamoto et al.[20]have reported that the thermore-ceptor TRPM2is expressed on the surface of keratinocytes and plays the role of sensing ROS in the surrounding environment.In response to ROS,these receptors create holes in the cell surface through which Ca 2?ions flow into the keratinocytes.The rise of the intracellular Ca 2?ion concentration due to this influx induces chemokine pro-duction.This mechanism is thought to be responsible for the increase in chemokine production in HFS-affected tissues.Chemokine production alone is not sufficient to produce the typical HFS state of inflammation.Moreover,it is thought that chemokines do not directly induce keratino-cyte apoptosis,but,rather,death factor cytokines are a necessary intermediary.Death factors known to induce apoptosis include TNF-a ,Fas ligand,lymphotoxin a ,TNF-related apoptosis-inducing ligand (TRAIL)/Apo2ligand,and Apo3ligand [21].Chemokines induce positive che-motaxis in blood cells,which express these death factors.For example,neutrophils expressing Fas ligand migrate to the dermis in response to chemokines produced by kerati-nocytes.These neutrophils undergo apoptosis in response to ROS,and at the same time caspase-1is activated inside the neutrophils,and IL-1b is released from the cells [22].While our fluorescent staining did not show this migration of blood cells (Fig.2),despite the presumably high level of chemokine production,it is thought that these cells may have undergone apoptosis and been taken up by macro-phages,which would explain their absence in the tissue staining photographs.The prevailing view up until now was that cells under-going apoptosis do not induce inflammation because they are absorbed by phagocytes or surrounding cells;however,the apoptosis of cells expressing death factors is a different matter.It is known that keratinocytes also express death factors [22],and it is thought that blood cells and kerati-nocytes undergoing apoptosis due to the presence of ROS cause inflammation by releasing IL-1b .Our results indicate that fibroblasts also produce IL-1b in response to ROS stimulation,and keratinocytes produce IL-1a and IL b inaFig.8Rescue of DOX/Cu(II)-induced decline in HaCaT cell survival rate by SOD.The values are presented as mean ±SD (n =3).Significantly different from DOX,DOX ?CuCl 2,and DOX ?CuCl 2?SOD,respectively:*p \0.05,*p \0.0116N.Yokomichi et al.。
手足综合征
手足综合征定义：手足综合征（HFS）又称掌跖感觉丧失性红斑综合征，是指某些化疗药物在手足部毛细血管渗出引致周围组织损伤的不良反应。
临床表现：为手掌和脚掌皮肤发红、肿胀、刺痛或灼热感、触痛及皮疹，并有行走和抓物困难，严重时还会出现水痘、皮肤皲裂或表皮脱落、水疱、溃疡、剧烈疼痛、腐烂或全层皮肤坏死。
为化疗药物引起的一种皮肤毒副作用。
HFS通常发生在化疗用药后3d—10个月，停药后症状逐渐消退，再次用药症状再次出现。
分级:根据美国国立癌症研究所（NCI）分级标准对手足综合征分为3级I级:手和（或）足麻木、感觉迟钝/感觉异常、麻刺感、无痛性肿胀、红斑和/或不影响正常活动的不适。
II级：手和（或）足疼痛性红斑、肿胀和/或影响正常生活的不适。
III级：手和（或）足出现脱屑、溃疡、水泡或严重疼痛和（或）使患者不能正常工作或生活的严重不适。
易引起手足综合征的药物：化疗药：卡培他滨、5-fu、阿霉素、阿糖胞苷、表柔比星、脱氧氟尿嘧啶、羟基脲、环磷酰胺、多西他赛、长春瑞滨、吉西他滨等。
靶向药物：索尼替尼（索坦）、索拉菲尼（多吉美）、伊马替尼（格列卫）、厄洛替尼（特罗凯）机制：尚不完全清楚1.炎性学说：可能与cox-2过度表达有关。
Tp酶（胸腺嘧啶磷酸化酶）及dpd酶（双氢嘧啶脱氢酶）手掌部位高表达，容易接受更多的细胞毒性药物。
dpd酶是一种内生嘧啶，是5-fu分解代谢的限速酶，影响5-fu抗肿瘤活性及毒性反应。
2.细胞毒作用直接损伤学说：手和足是日常生活活动比较多的部位，在平时生活中会造成较小的损伤，导致毛细血管等产生微小的破损，从而造成化疗药物的渗出。
另一方面，汗腺是化疗主要受损组织，手足分布的密度大大高于身体其他部位。
3.维生素B6缺乏学说4.基因学说治疗：1.减少药物剂量：hfs是剂量依赖性反应2.局部冷敷：血管收缩，从而限制循环药物到达四肢，同时减少药物的外渗3.维生素B6：希罗达治疗同时合并使用大剂量维生素B6（300mg/天），能够预防及治疗，包括软膏及片剂4.止汗剂：定期使用，减少汗液分泌或者局部使用氯化铝可以预防。
手足综合征ppt课件
HFS
34 % 36 % 6–37 % 22–26 % 40–50 % 34–48 % 50–60 % 6–13 % 56–63 % 89 %
严重HFS（≥3级）
G2/3: 30 %，G3: 9 % 23 % 0–4 %
Grade 2/3: 20 % 2–5 %
10–17 % 0.5 %
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发病规律（1）
综合多项国外大样本Ⅱ/Ⅲ期研究，卡培他滨相关性手足综合征 的发生率多在48%～62%，最高亦有74%的报道，而3～4级的 发生率在10%～24%。
HFS通常是自限性的，是否具有累积性尚不明确。
HFS在治疗的1～4个周期(中位2个周期) 中出现，而且药物减量 可以影响HFS的自然病程。
18
HFS及HFSR发病机制
卡培他滨 脂质体阿霉素 索拉菲尼和舒尼替尼
19
卡培他滨
由于手掌皮肤的胸苷磷酸化酶 （TP酶）高表达，二氢嘧啶脱 氢酶（DPD酶）低表达，这可 能导致卡培他滨代谢产物的蓄 积，造成HFS发生率的增加； 手掌高表达Ki-67，对化疗药更 敏感。
卡培他滨可能经由外分泌腺系 统（汗腺）排出，而手和足部 的外分泌腺体数量较多，在这 些部位进行的卡培他滨的排泄 可能是造成HFS的原因；
• 2级：手和/或足的疼痛性红斑和肿胀和/或影响患者日常活动的 不适。
• 3级：手和/或足湿性脱屑、溃疡、水疱或严重的疼痛和/或使患 者不能工作或进行日常活动的严重不适。痛感强烈，皮肤功能 丧失，比较少见。
7
NCI 标准*：1级HFS症状
1级:麻木、感觉迟钝/感觉异常、针刺感、手或足出现无痛性肿胀 或红斑或不适（但并不影响正常活动）。
在皮肤的TP酶高表达使卡培他滨局部活化，而在掌区的低DPD 酶水平可以解释为何在掌部优先、特异地发生HFS。
卡培他滨致手足综合征的中西医治疗进展
卡培他滨致手足综合征的中西医治疗进展摘要：卡培他滨是一种具有类似氟尿嘧啶作用的一种口服化疗药物，在体内可以通过多种酶的共同作用转化为5-氟尿嘧啶，从而发挥抗肿瘤的细胞毒作用。
并且被广泛应用于乳腺癌、消化道肿瘤等。
常见胃肠道反应，手足综合征，骨髓抑制等不良反应，其手足综合征是相对比较突出的不良症状，严重的手足综合征不仅可以影响患者的生活质量，也可以导致化疗终止或化疗延期，从而影响到患者的治疗。
下面笔者就对近年卡培他滨所致手足综合征的中西医治疗及预防进展作简要的综述，希望对未来的治疗能有所帮助。
关键词：卡培他滨；手足综合征；中西医治疗1.正文卡培他滨是一种对肿瘤细胞有选择性活性的新型口服细胞毒药物，其在人体肝脏和肿瘤细胞中通过羧酸酯酶等酶转化为具有细胞毒性的5-氟尿嘧啶，发挥抗肿瘤作用，具有不良反应少、疗效确切等优点，在临床中被广泛应用于乳腺癌、结直肠癌、胃癌、食管癌等治疗[1-2]。
手足综合征虽然不会威胁患者的生命，但是会严重影响患者的生活质量以及患者的治疗，影响化疗的疗效及预后。
手足综合征的临床表现主要为麻木或针刺感、感觉异常或迟钝、无痛或疼痛感，皮肤肿胀或红斑，脱屑、水泡或严重的疼痛等。
手足综合征诊断依据为：①有使用氟尿嘧啶衍生物、脂质体包裹的阿霉素等化疗药物史；②潜伏期11～360 d，平均7g d；③手和（或）足出现感觉丧失性红斑；④病情分Ⅲ度，I度为手和（或）足麻木，感觉迟钝和（或）感觉异常，有麻刺感，无痛性肿胀、红斑和（或）无任何不适；II度为手和（或）足有疼痛性红斑，可影响患者日常生活；Ⅲ度为手和（或）足出现脱屑、溃疡、水疱或严重疼痛，影响患者工作或进行日常活动[3]。
宋芳华等[4]用维生素B6联合甲钴胺片防治卡培他滨所致手足综合征的临床观察中，结果治疗组手足综合征发生率为25.0％（10/40），对照组为47.2％（17/36），差异有统计学意义（p<0.05），口服维生素B6和甲钴胺片可以提高卡培他滨的用药安全性及疗效。
手足综合征概述PPT课件
相关检查
1.心电图：左室肥大伴复极异常，心脏彩超： EF48%（2015.9.25为62%），提示射血分数较 前下降。 2.尿常规：潜血阳性，蛋白3+。
3
诊疗经过
1.心电监测、吸氧。 2. 止痛治疗:吗啡注射液皮下注射；吗啡栓剂
应用；口服羟考酮缓释片，10毫克 Q12h。 3.心脏毒性治疗：口服单硝酸异山梨酯片。 4.手足综合征：停止口服艾坦；外用扶他林
肿瘤病人在接受化疗或分子靶向治疗的过程 中可出现。
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临床表现
HFS的特征表现为麻木、感觉迟钝、感觉异常、 麻刺感、无痛感或疼痛感，皮肤肿胀或红斑， 脱屑、皲裂、硬结样水泡或严重的疼痛等。
根据美国国立癌症研究所（NCI）分级标准 对手足综合征分为三级。
14
分级
根据美国国立癌症研究所（NCI）分级标准对 手足综合征分为三级。
10
导管护理措施
1.加强交接班，准确记录导管留置长度。 2.每日观察穿刺处有无渗血、渗液，测量臂
围，定时更换贴膜以及正压接头，导管贴 膜松动及时更换，妥善固定。 3.向患者做宣教，告知患者活动时避免导管 牵拉。
11
手足综合征
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概念
手足综合征（hand foot syndromes,HFS）: 是手掌-足底感觉迟钝或化疗引起的肢端红 斑,是一种皮肤毒性。
2.加强与患者沟通，指导患者通过阅读、听广 播、听音乐等方式转移注意力以缓解疼痛 。
3.尽可能满足患者对舒适的要求，保持室内环 境安静、整洁、舒适。
8
护理措施-心理焦虑
1.加强与患者沟通，注意观察患者情绪变化， 及时了解患者心理需求并满足。
2.向患者讲解必要的疾病知识，缓解患者紧张 焦虑情绪，增强患者治疗的信心。
卡培他滨相关手足综合征的治疗进展
保持手足皮肤湿润 可有助于预防和使 病灶早日痊愈，涂 上护肤霜，如：凡 士林软膏等。避免 在阳光下曝晒，涂 防晒霜。
在家可以穿拖鞋， 坐著或躺著的时候 将手和脚放在较高 的位置、避免进食 辛辣、刺激性食物。 修剪过长指甲，穿 戴手套软袜。
日常洗簌避免太 勤，避免抓挠。 出现脱皮时不要 用手撕，可以用 消毒的剪刀剪去 掀起的部分。
生物制剂
大剂量白细胞介素-2
日本癌症研究基金会（JFCR）癌症研究所附属医院《乳腺癌研究与治疗》
手足综合征分级：
美国国立癌症研究所（ＮＣＩ）分级标准
加拿大国立癌症研究院（ＣＴＧ）分级标准
HFS的发展与卡培他滨 的累积剂量呈正相关
丰山，T.，Yoshimura，A.，Hayashi，T.等.乳腺癌(2018年)25：729
化疗相关手足综合征的发病机制
第一种：手足综合征的发生与手足血管的炎性反应具有相关性，这种炎性反应─皮肤细胞毒性的发生，可能是 直接或间接由卡培他滨或其代谢产物而导致的。这种反应与ＣＯＸ－２酶的过度表达有关。
第二种：认为卡培他滨在人体内的代谢是通过小汗腺排出的，与其他部位相比，手部与足部更多有的小汗腺。
卡培他滨相关手足综合征的治疗进 展
什么是手足综合征？
手足综合征（ＨＦＳ）又称掌趾感觉丧失性红斑综合征，是一种特征性的皮肤毒性反应。
主要临床表现为手和（或）足的麻木，感觉迟钝，感觉异常，如针刺感，烧灼感，无痛性或疼痛性的红斑肿胀，干燥， 脱屑，严重者出现溃疡，水疱，表皮脱落，脱皮，脱甲，出血，剧烈疼痛，并且伴有行走和抓物困难，影响日常工作 生活。
手足综合征和手足皮肤反应：
发生诱因
手足综合征（ＨＦＳ） 传统化疗药（卡培他滨、氟尿嘧啶等）
手足皮肤反应（ＨＦＳＲ） 多激酶抑制剂（索拉菲尼、拉帕替尼等）
手足综合征治疗及护理
[4]董元鸽 陆箴琦 杨瑒 . 手足综合征病人生活质量量表的研究进 展 [J]. 护理研究, 2015,(34) .doi:10.3969/j.issn.10096493.2015.34.006 .
THANK YOU！
• HFS通常发生在化疗用药后多长时间？
（3天-10个月）．停药后症状逐渐消退．再次用药症状再次出现。
药物
• 希罗达 • 多柔比星脂质体 • 5-氟尿嘧啶 • 多西他赛 • 替加氟
1. 手足综合征的定义 2. 手足综合征的分级 3. 手足综合征的护理
课堂目标
分级
根据美国国立癌症研究所(NCI)分级标准对手足综合征分为3级：
生素E、环加氧酶抑制剂、中药等。
治疗
• 维生素B6 希罗达治疗同时合并使用大剂量维生素
B6(300mg/d)。
• 塞来昔布 目前认为基于HFS的病理表现，考虑是一种炎性反应，
可能和环氧化酶过于表达有关，环氧化酶特异性抑制剂可能有 助于预防HFS或HFS的程度。
• 糖皮质激素 糖皮质激素与脂溶性维生素合用，可促进脂质的抗
• 制订营养计划，每日更换食物品种，促进食欲，达到营养均衡。
确保每天饮水量>2500ml。保持大、小便通畅，以促进体内药物 排泄，减少对机体的伤害。
参考文献
[1]林雅芳，林朝春，林云月．乳腺癌患者使用多柔比星脂质体所 致手足综合症的护理[J].大家健康(学术版)，2013，(7)：234235．
[2]许丽媛，梁莹．30例化疗致手足综合症的护理[J].中日友好医 院学报，2013，27(2)：126—127．
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发病规律（1）
➢ 综合多项国外大样本Ⅱ/Ⅲ期研究，卡培他滨相关 性手足综合征的发生率多在48%～62%，最高亦 有74%的报道，而3～4级的发生率在10%～24%。
➢ HFS通常是自限性的，是否具有累积性尚不明确。 ➢ HFS在治疗的1～4个周期(中位2个周期) 中出现，
而且药物减量可以影响HFS的自然病程。 ➢ 3级HFS的中位持续时间是13天，在中断治疗后
• 炎性改变、血管扩张、 水肿和白细胞浸润。
• 电镜下可见小神经纤 维病变。
病理特点（2）
• 大量或单层角化细胞坏 死。
• 表皮下、表皮内坏死， 角质层水泡形成，并伴 角化过度或角化不全的 棘皮症。
• 少数病例可有腺体的囊 性变，甚至有些腺体发 生鳞状细胞化生。
• 可见淋巴细胞浸润和毛 细血管扩张。
危险因素
➢ Abushullaih等研究发现较高的行为状态 （higher performance status）与HFS的发病 相关（P=0.0029）。
➢ Heo等发现联合多西紫杉醇是唯一的独立危 险因素。早于HFS出现的化疗相关性口腔炎与 HFS的发生相关（P=0.0029）。
危险因素
脂质体阿霉素发生HFS危险因素
索拉菲尼和索尼替尼
• 表皮角化细胞可以合 成PDGF-α和PDGF-β, 这些因子可活化真皮 毛细血管、纤维母细 胞和分泌腺表面的 PDGFR。
• 外分泌腺还表达c-kit和 PDGFR。索拉菲尼和 索尼替尼正好抑制这 些靶点，导致血管修 复机制失常。
治疗
一般治疗
药物剂量调整
药物治疗
• COX-2抑制剂：塞来昔布（西乐葆） • 维生素B6 300mg/d • 维生素E • 局部外用药物 ：10%尿嘧啶油膏、尿素霜、
谢谢!
维生素E
➢ Kara等使用卡培他滨联合多西紫杉醇方案 治疗转移性乳腺癌。
• 5例患者均出现2～3级HFS。 • 给予Vit E（300mg/d）口服治疗1周后，
症状减轻，且5例患者均无减量用药情况 。
尿素霜（角质层分离剂）
• Pendharkar等观察13例出现2～3级卡培他 滨相关性HFS的患者。
• 脂质体阿霉素应用周期 • 黏膜炎 • 中性粒细胞减少 • 外周神经病变
发病机制
卡培他滨
➢ 由于皮肤的胸苷磷酸化酶（TP 酶）高表达和二氢嘧啶脱氢酶 （DPD酶）低表达，这可能导 致卡培他滨代谢产物的蓄积， 造成HFS发生率的增加；
➢ 卡培他滨可能经由外分泌腺系 统（汗腺）排出，而手和足部 的外分泌腺体数量较多，在这 些部位进行的卡培他滨的排泄 可能是造成HFS的原因；
迟钝、麻木，皮肤粗糙、皲裂 ➢ 可有手指皮肤切指样皮肤破损，出现水泡、脱屑、
脱皮、渗出、甚至溃烂，并可能继发感染。患者 可因剧烈疼痛而无法行走 ➢ 可导致丧失生活自理能力。 自限性，但再次给药后会再次出现。
分级标准
• NCI分级标准 • WHO分级标准 • 加拿大国立研究所CTC常用毒性分级标准
NCI分级标准
下降1～2级， • 1例观察到皮肤过敏反应（表现为非典型
白色小丘疹），未见全身过敏反应。
中医中药
常用外洗方推荐： ➢ 皮损明显者：丹皮15克，冰片3克，苦参15克，
徐长卿15克，山慈菇15克，赤芍15克，野菊花15克， 蒲公英15克，紫花地丁15克，紫草20克。 ➢ 手足麻木者：海风藤15克，赤芍15克，路路通 30克，山慈菇15克，三棱15克，莪术15克，川芎10 克，木通10克。 ➢ 皮肤瘙痒者：蛇床子15克，地肤子15克，防风 15克，赤芍15克，蝉蜕10克，生地30克，白蒺藜15 克，丹皮15克。 ➢ 四肢不温者：桂枝10克，川芎10克，路路通15 克，元胡10克，红花10克，赤芍15克，当归10克。
• 两组的HFS发病率无显著差异（观察组63% vs 对照组53%）。
• 使用VitB6治疗组的治疗获益率明显高于对照组 （观察组65% vs 对照组12%），差异有显著性 （P＜0.001）。
➢ 回顾性研究分析：卡培他滨治疗同时配合口服大 剂量VitB6（300mg/d) 可使HFS的严重程度有所 减轻，且对疗效无明显不利影响。
➢在皮肤的TP酶高表达使卡培他滨局部活化， 而在掌区的低DPD酶水平可以解释为何在 掌部优先、特异地发生HFS。
脂质体阿霉素
• 亲皮肤性、亲肿瘤性 • 鼠模型发现在其爪部的药物浓度较皮肤部
位高。 • 应用荧光定位监测发现用药3小时后在皮肤
浓度高的部位：前臂屈侧、手掌、脚底、 腋窝和前额。主要在汗腺深部（亲水性）。 • 在角质层底部向下渗透后形成自由基攻击 表皮细胞形成HFS。
➢ HFS的发生可能与手和足部的 血运丰富及局部压力、温度较 高有关；
➢ 基于HFS的病理表现，考虑是 一种炎性反应，可能和环加氧 酶（COX-2）过表达有关。
DPD酶多态性与手足综合征
手掌DPD酶活性低
➢Ferrero等对比观察12名健康志愿者的皮肤 活检，以手掌皮肤为观察区、手背皮肤为 对照区，DPD酶在对照组中的表达要明显 高于观察组。TP酶在观察组和对照组的基 底层均有显著表达。
二甲亚砜 • 地塞米松 8mg po bid • 中医中药调理或外洗 • 用药期间局部冰敷
卡培他滨+塞来昔布vs 卡培他滨
观察组
对照组
P值
手足综合症 12.5%
34.3%
0.037
腹泻
3.1%
28.6%
0.005
TTP
6月
3月
0.002
维生素B6
➢ 美国一项12个门诊中心198例患者的回顾性汇总 分析，评估了VitB6对卡培他滨相关性HFS的预防 作用。
WHO分级标准
1级
பைடு நூலகம்
2级
3级
4级
手足感觉迟 持物或行走 掌和跖部痛 脱屑, 溃疡,
钝撼觉异常，时不适，无 性红斑和肿 水疱, 剧烈
麻刺感；可 痛性肿胀或 胀, 甲周红 疼痛, 可见
见红斑，组 红斑，还可 斑和肿胀, 水疱, 组织
织学可见表 出现红肿 。 可见皮肤皲 学示表皮完
皮网状组织
裂, 组织学 全坏死。
血管扩张 。
表皮见孤立
坏死的角质
细胞。
加拿大国立癌症研究所CTC标准
I度
Ⅱ度
Ⅲ度
麻木、感觉迟钝 痛性肿胀和／或 湿性脱屑、溃疡、
或感觉异常，无 红斑，影响日常 水泡和／或疼痛，
痛性肿胀和／或 生活。
无法进行日常生
红斑，不影响日
活。
常生活。
病理特点（1）
• 基底角质细胞空泡变 性、皮肤血管周围淋 巴细胞浸润、角质细 胞凋亡和皮肤水肿。
手足综合征机制及防治进展
河南省肿瘤医院 郭宏强
• 手足综合征（HFS）：又称为掌跖感觉丧 失性红斑（PPES），临床主要表现为指/趾 的热、痛、红斑性肿胀，严重者发展至脱 屑、溃疡和剧烈疼痛，影响日常生活。
• 1984年就由哈佛医学院英格兰戴肯尼斯医 院的Jacob Lokich和Chery Moore进行了报 道，当时观察到在长期反复接受5-Fu或脂 质体阿霉素化疗的患者中有25%发生这种 特异性的皮肤综合征。
HFS是可逆的，而且减量对于2～3级的患者可以 有效地预防复发。
发病规律（2）
• 脂质体阿霉素发生HFS率50%，20%为3-4 度。
• 在应用化疗后2-12天出现。 • 与剂量及滴注时间相关。
发病规律（3）
• 索拉菲尼：发生率33.8%，重度8.9% • 索尼替尼：发生率18.9%，重度5.5% • 一般在服用药物2-4周出现。
• 使用尿素霜外涂局部，每天两次，在使用 2～3天后开始起效，可明显减轻脱屑、疼 痛、不适的症状。
• 所有患者均按计划完成化疗，无停药及减 量情况。
10%尿嘧啶油膏
➢Netikova等采用10%尿嘧啶油膏外用治疗 5-Fu/卡培他滨相关性HFS，局部外用，每 天2～3次 。
➢可评价疗效病例68例： • 34%（23/68）无效， • 66%（45/68）在治疗2～4周后HFS分级
易引起手足综合征的药物
• 化疗药：卡培他滨、脂质体阿霉素、阿糖胞苷、 多西紫杉醇、长春瑞滨、持续输注 阿霉素、吉西他滨等
• 靶向药物：索尼替尼（索坦）、索拉菲尼（多 吉美）、伊马替尼（格列卫）、厄 洛替尼（特罗凯）
• 生物制剂：大剂量IL-2
临床表现
一种进行性加重的皮肤病变，手较足更易受累 ➢ 手掌和足底皮肤瘙痒，手掌、指尖和足底充血 ➢ 指/趾末端疼痛感，手/足皮肤红斑、紧张感，感觉