Oral Anticancer Drug Research Articles

No clinically significant drug interactions between lenalidomide and P-glycoprotein substrates and inhibitors: results from controlled phase I studies in healthy volunteers

PurposeLenalidomide, a weak substrate of P-glycoprotein (P-gp) in vitro, is an oral anticancer drug eliminated predominantly via renal excretion as unchanged compound. The role of P-gp in lenalidomide disposition and the associated clinical relevance were evaluated.MethodsTwo phase I, crossover studies were conducted in healthy volunteers. In Study 1, subjects received lenalidomide (10 mg × 7 days) alone or with the P-gp substrate digoxin (0.5 mg on Day 5). In Study 2, subjects received lenalidomide (a single 25 mg dose) alone, the P-gp inhibitor quinidine (300–600 mg twice-daily × 5 days) plus lenalidomide (on Day 4), the P-gp inhibitor/substrate temsirolimus (a single 25 mg dose) alone, or lenalidomide plus temsirolimus. Pharmacokinetic and safety data were collected for lenalidomide and the co-administrated drugs.ResultsThere were no significant changes in the maximum concentration (C max) and area under the plasma concentration–time curve (AUC) of lenalidomide when co-administered with quinidine, digoxin, or temsirolimus. Neither the rate nor the capacity of lenalidomide renal excretion was affected by quinidine or temsirolimus, in addition lenalidomide absorption rate and bioavailability remained unchanged. Furthermore, lenalidomide had no significant effect on blood C max and AUC of temsirolimus and its active metabolite sirolimus (also a P-gp inhibitor/substrate). The C max of digoxin was slightly higher (+14 %) when administered with lenalidomide versus placebo. There were no other changes in digoxin pharmacokinetics upon co-administration with lenalidomide. No remarkable safety findings were observed.ConclusionsThere are no clinically significant pharmacokinetic interactions between lenalidomide and substrates or inhibitors of P-gp.

Immobilization of Coacervate Microcapsules in Multilayer Sodium Alginate Beads for Efficient Oral Anticancer Drug Delivery

We have designed and evaluated coacervate microcapsules-immobilized multilayer sodium alginate beads (CMs-M-ALG-Beads) for oral drug delivery. The CMs-M-ALG-Beads were prepared by immobilization of doxorubicin hydrochloride (DOX) loaded chitosan/carboxymethyl coacervate microcapsules (DOX:CS/CMCS-CMs) in the core and layers of the multilayer sodium alginate beads. The obtained CMs-M-ALG-beads exhibited layer-by-layer structure and rough surface with many nanoscale particles. The swelling characteristic and drug release results indicated that 4-layer CMs-M-ALG-Beads possessed favorable gastric acid tolerance (the swelling rate <5%, the cumulative drug release rate <3.8%). In small intestine, the intact DOX:CS/CMCS-CMs were able to rapidly release from CMs-M-ALG-Beads with the dissolution of ALG matrix. Ex vivo intestinal mucoadhesive and permeation showed that CMs-M-ALG-Beads exhibited continued growth for P(app) values of DOX, which was 1.07-1.15 folds and 1.28-1.38 folds higher than DOX:CS:CMCS-CMs in rat jejunum and ileum, respectively, demonstrating that CMs-M-ALG-Beads were able to enhance the absorption of DOX by controlled releasing DOX:CS/CMCS-CMs and prolonging the contact time between the DOX:CS/CMCS-CMs and small intestinal mucosa.

Oral absorption mechanism and anti-angiogenesis effect of taurocholic acid-linked heparin-docetaxel conjugates

Oral delivery is the preferred route to deliver therapeutics via nanoparticles due to ease of administration and patient acceptance. Here, we report on the findings of the absorption pathway of taurocholic acid (TCA)-linked heparin and docetaxel (DTX) conjugate, which we refer to as HDTA. We studied the oral absorption of HDTA using a Caco-2 cell transport system and an animal model. We have also used other absorption enhancers, such as ethylene glycol tetraacetic acid (EGTA), or inhibitors, such as sodium azide, to compare the relative permeability of HDTA conjugates. In vivo comparative studies were conducted using free TCA as a pre-administration and exhibited the maximum absorption site of the organ after oral administration of HDTA conjugates. HDTA was found to be absorbed mainly in the ileum and Caco-2 cell monolayer through passive diffusion and bile acid transporters. High fluorescence intensity of HDTA in mice came from the ileum, and it was eliminated from the body through colon. This novel formulation could be further investigated by clinical trials to find the prospect of oral anti-cancer drug delivery through anti-angiogenic treatment strategies.

Improving the oral delivery efficiency of anticancer drugs by chitosan coated polycaprolactone-grafted hyaluronic acid nanoparticles.

Sequentially overcoming the obstacles mainly from the low water solubility of lipophilic anticancer drugs, gastrointestinal microenvironment and systemic circulation is the major concern for designing oral anticancer drug carriers. Herein, we prepared the multifunctional polyelectrolyte complex nanoparticles (CNPs), engineered by hyaluronic acid (HA) grafted polycaprolactone (PCL) nanoparticles (HA-g-PCL NPs) coated with chitosan (CS) electrostatically, as a platform to improve the oral delivery efficiency of lipophilic anticancer drugs. Paclitaxel (PTX) and doxorubicin (DOX) were used as the model medicine and fluorescence probe, respectively. The size, zeta potential, morphology and pH-sensitivity of the NPs were studied systematically. The results indicated that the core-shell structure of CS/HA-g-PCL CNPs was formed at pH 5.0, which remained intact in the pH ranging from 3.0 to 6.8, while the CS layer detached gradually with the increase of pH to 7.4 and the HA-g-PCL NPs were released. In vitro drug release studies showed that accelerated drug release was triggered by hyaluronidase-1 (Hyal-1), which was a major HA degradation enzyme abundant within tumor cells. Cell uptake studies showed that HA-g-PCL NPs were internalized into cancer cells (EC109) via receptor-mediated endocytosis, but were rarely taken up by normal fibroblasts (NIH3T3). Furthermore, intracellular drug release indicated that HA-g-PCL NPs could provide an effective approach for transport of loaded cargoes into the cytoplasm. Therefore, higher cytotoxicity for PTX loaded HA-g-PCL NPs (HA-g-PCL/PTX NPs) against cancer cells EC109 but lower cytotoxicity against normal cells NIH3T3 was observed. In vivo studies showed that CS/HA-g-PCL CNPs via oral administration were able to preferentially deliver drugs into tumor tissue with commendable antitumor efficiency and few side effects. Overall, CS/HA-g-PCL CNPs showed great potential for improving oral delivery efficiency of lipophilic anticancer drugs.

Immunoprotective Effect of Epigallocatechin-3-gallate on Oral Anticancer Drug-Induced α-Defensin Reduction in Caco-2 Cells

The aim of this study was to determine the effect of interaction between tegafur (FT) and epigallocatechin-3-gallate (EGCG) on the expression of α-defensins (HD-5: human α-defensin 5, HD-6: human α-defensin 6) by using a Caco-2 cell line as a model of human intestinal epithelial cells. This is the first study in which the effect of interaction of an oral anticancer drug and functional food on the innate immune system was examined. α-Defensins are abundant constituents of mouse and human paneth cells and play a role in the innate immune system in intestine. We detected HD-5 and HD-6 mRNA in Caco-2 cells and evaluated the effects of FT and EGCG on these mRNA levels. HD-5 and HD-6 mRNA levels were decreased by exposure to FT. Production of reactive oxygen species (ROS) was induced by exposure to FT as well as H2O2 exposure, and EGCG suppressed FT-induced production of ROS. Furthermore, FT-induced decrease in HD-5 and HD-6 mRNA levels was almost completely suppressed by EGCG. These results indicate that EGCG restored the decrease of α-defensins induced by FT at the transcriptional level in Caco-2 cells, suggesting that EGCG can be used as adjunctive therapy in chemotherapy.

Adverse Effects of the Oral Anticancer Drug S-1: Lacrimal Passage Impairment and Specific Features of Corneal Epitheliopathy

We report the incidence of lacrimal passage impairment and specific features of corneal epitheliopathy as adverse effects of the oral anticancer drug S-1, and examine the relationship between the two pathologies. We conducted a retrospective chart review of 84 patients prescribed the anticancer drug S-1. The incidence of lacrimal passage impairment and corneal epitheliopathy was 8% and 6%, respectively. Three patients experienced both pathologies, demonstrating a moderate probability of both occurring in the same patient (kappa coefficient = 0.46). The findings show that lacrimal passage impairment and specific features of corneal epitheliopathy are likely to occur in the same individual as adverse effects of S-1.

Bioequivalence study designs for generic solid oral anticancer drug products: Scientific and regulatory considerations

The demonstration of bioequivalence (BE) between the test and reference products is an integral part of generic drug approval process. A sound BE study design is pivotal to the successful demonstration of BE of generic drugs to their corresponding reference listed drug product. Generally, BE of systemically acting oral dosage forms is demonstrated in a crossover, single-dose in vivo study in healthy subjects. The determination of BE of solid oral anticancer drug products is associated with its own unique challenges due to the serious safety risks involved. Unlike typical BE study in healthy subjects, the safety issues often necessitate conducting BE studies in cancer patients. Such BE studies of an anticancer drug should be conducted without disturbing the patients' therapeutic dosing regimen. Attributes such as drug permeability and solubility, pharmacokinetics, dosing regimen, and approved therapeutic indication(s) are considered in the BE study design of solid anticancer drug products. To streamline the drug approval process, the Division of Bioequivalence posts the Bioequivalence Recommendations for Specific Products guidances on the FDA public website. The objective of this article is to illustrate the scientific and regulatory considerations in the design of BE studies for generic solid oral anticancer drug products through examples.

Chitosan/o-carboxymethyl chitosan nanoparticles for efficient and safe oral anticancer drug delivery: In vitro and in vivo evaluation

The present study investigated the ability of a polyelectrolyte complex (CS/CMCS-NPs), composed of chitosan (CS) and o-carboxymeymethy chitosan (CMCS) as a pH responsive carrier for oral delivery of doxorubicin hydrochloride (DOX). The obtained CS/CMCS-NPs were characterized for various parameters including morphology, particle size, zeta potential, entrapment efficiency and stability under the simulated GI tract conditions. The pH responsive stability of the DOX-loaded CS/CMCS nanoparticles (DOX:CS/CMCS-NPs) determined the drug release rate, which was lower in acidic pH than the neutral. Ex vivo intestinal adhesion and permeation indicated DOX:CS/CMCS-NGs were able to enhance absorption of DOX throughout the entire small intestine, especially in jejunum and ileum. Oral administration of DOX:CS/CMCS-NPs was effective to deliver DOX into blood, giving an absolute bioavailability of 42%. The tissue distribution and toxicity of DOX:CS/CMCS-NPs in rats showed low level of DOX in heart and kidney, and obviously decreased cardiac and renal toxicities. These results indicated CS/CMCS-NPs were highly efficient and safe as an oral delivery system for DOX.

Lymph node ratio is a critical prognostic predictor in gastric cancer treated with S-1 chemotherapy

S-1 is an oral anticancer drug widely used in postoperative adjuvant therapy for patients in Japan with stage II/III gastric cancer. Candidates for more intense adjuvant treatments need to be identified, particularly among patients with stage III cancer. Univariate and multivariate analyses were conducted for patients with stage II/III gastric cancer who underwent surgery and received S-1 postoperatively between 2000 and 2010. Factors indicating poor prognosis identified by univariate analysis include male sex (P = 0.022), age ≥67 years (P = 0.021), intestinal-type histology (P = 0.049), lymph node ratio ≥16.7 % (P < 0.0001), open surgery (P = 0.039), as well as the 13th JGCA stage (P < 0.0001) and the 14th JGCA/7th International Union Against Cancer (UICC) stage (P < 0.0001). Multivariate analysis revealed that lymph node ratio ≥16.7 % and intestinal-type histology were significant as predictors of prognosis, independent from the pathological stages. Based on these and other findings, stage IIIC cancer on the 14th JGCA/7th UICC stage system in combination with the lymph node ratio could identify patients with extremely high risk for recurrence Our current findings suggest that lymph node ratio ≥16.7 % in combination with the new staging system could be a useful prognostic indicator in advanced gastric cancer. Because these high-risk patients cannot be identified preoperatively by any diagnostic tool, further improvement in postoperative adjuvant therapy is warranted.

High efficacy of combination chemotherapy with S-1 and low-dose docetaxel for the treatment of highly advanced gastric cancer with peritoneal dissemination: A case report

S-1 has been developed as a new oral anticancer drug based on the biological modulation of 5-fluorouracil. We treated a patient with highly advanced gastric carcinoma with a new combination chemotherapy of S-1 and low-dose docetaxel. Evident tumor reduction was observed following two cycles of this therapy in the primary tumor and metastatic lymph nodes. This was concluded to be a partial response. The gastric tumor exhibited significant invasion to the serosa. Lymph nodes around the stomach were swollen. Peritoneal dissemination was also identified in the mesocolon. Palliative resection of part of the distal stomach and dissection of regional lymph nodes were performed. Histological examination demonstrated that no tumor cells were detected in the greater omentum, suggesting pathological complete remission. It is suggested that this regimen may provide a potent combined therapy for the treatment of patients with highly advanced gastric carcinoma and it may be useful as an adjuvant chemotherapy. Further studies are necessary to evaluate the efficacy of this therapy.

Tegafur/gimeracil/oteracil (TS-1) induced Stevens–Johnson syndrome: Case report

TS-1 is an oral fluoropyrimidine anticancer drug that contains tegafur, gimeracil, and oteracil. A 78-year-old Japanese male who was diagnosed with carcinoma of the oral floor (rT4aN0M0) was prescribed a standard dose of TS-1 (80 mg/day). On Day 8 after administration of TS-1, an eruption developed. There was erythema, along with vesicles and erosions involving the lip, face, neck, trunk, limbs, and genitals. The drug-induced lymphocyte stimulation test (DLST) for TS-1 was negative on the 23 rd day, but positive on the 43 rd day (20 days after discontinuing prednisolone). The condition was diagnosed as Stevens–Johnson syndrome due to TS-1 because of the clinical course and laboratory results. This case and 24 cases previously reported in the literature were analyzed. The types of drug eruption were drug-related lupus (9 cases), acral erythema (7 cases), scleroderma-like skin lesion (2 cases), Stevens–Johnson syndrome (2 cases), lichenoid eruption (1 case), purpura (1 case), lichen planus (1 case), erythema multiforme (1 case), hypopigmentation (1 case) and toxic epidermal necrolysis (1 case), respectively. In view of the increasing usage of TS-1 in several common cancers, clinicians should be aware of drug eruptions due to TS-1.

Randomized, controlled trial comparing S-1 with UFT/LV as adjuvant therapy for curatively resected stage III colorectal cancer (BCOG-CC02 study).

520 Background: Oral anticancer drug, UFT/LV, has recently been reported to improve both overall survival (OS) and relapse free survival (RFS) for patients with Stage III colorectal cancer in Japan. We conducted a randomized clinical trial to compare S-1 with UFT/LV for adjuvant therapy in patients with Stage III colorectal cancer. Methods: Patients with Stage III colorectal cancer (PS, 0 to 1; age, 20 to 80 years) were randomized to take either UFT / LV (28 days per 5 weeks) for 6 months. or S-1 (28 days per 6 weeks) for 12 months started within 6 weeks following curative resection. We investigated the correlations between disease- free survival (DFS) and tissue mRNA levels of 5-FU and folate metabolism-related enzymes. In addition, we investigated overall survival (OS) and safety. Results: Between April 2008 and August 2010, a total of 145 patients were registered from 22 centers. There were no clear intergroup differences in background factors. The patients who relapsed during protocol duration of treatment were excluded, the percentages of patients who took expected dosage of medicine were 67.1% (47/70) and 87.3% (62/71) in S-1 and UFT/LV groups, respectively. Grade3 to 4 myelosuppression(4%), bilirubin(3%) and diarrhea(8%) were occurred in S-1 group whereas, grade 3 liver dysfunction (5%) and diarrhea (5%) occurred in UFT/LV group, but all of them were reversible. The median follow-up period was 934 days, 3-years’ DFS in patients of S-1 and UFT/LV groups were 65.9% and 72.7%, respectively (p=0.88). In a univariate analysis, topoisomerase-1 (TOPO-1) mRNA level was shown as a factor of the recurrences. A poor-prognosis patient population was observed in the S-1 group such as with low gamma-glutamyl hydrolase (GGH) mRNA level. Conclusions: Oral anticancer drug, S-1 showed an equivalent effect for UFT/LV in Stage III colorectal cancer as adjuvant therapy. Tissue levels of mRNA of 5-FU/ folate metabolism-related enzymes were important parameters for postoperative prognosis in patients with stage III colorectal cancer who take oral 5-FU derivatives for adjuvant therapy. Clinical trial information: UMIN000001560.

Phase I clinical trial of a peptide vaccine combined with tegafur-uracil plus leucovorin for treatment of advanced or recurrent colorectal cancer

Recently, analysis of tumor antigens using micro-arrays has revealed upregulation of cancer-testis antigens RNF43 and TOMM34 and vascular endothelial growth factor receptors VEGFR1 and VEGFR2 in colorectal cancer. A phaseI clinical trial of peptide vaccine therapy together with oral anticancer drugs was conducted to treat advanced colorectal cancer using synthesized peptides of these tumor antigens in order to confirm the safety, immunogenicity and activity of this treatment. The subjects were patients with a human leukocyte antigen (HLA) type of A2402 who had inoperable colorectal cancer but had failed to respond to or were unable to undergo standard chemotherapy. Four peptides (RNF43, TOMM34, VEGFR1 and VEGFR2) were emulsified with incomplete Freund's adjuvant (Montanide), and the resulting solution was administered subcutaneously once a week. Patients received the oral anticancer drug tegafur-uracil plus leucovorin for four weeks continuously as part of one course followed by one week of rest. The primary endpoint of the trial was observation of adverse events as determined by the NCI-CTCAE criteria, and the secondary endpoints were the size of the tumor and the number of cytotoxic Tlymphocytes (CTLs) in the peripheral blood after treatment. Vaccine therapy was administered 148times to 10patients from July2008 to December2009. The adverse events were grade 1 redness and induration, a grade2 skin ulcer at the vaccination site and grade 1 pyrexia. All patients tolerated treatment. Tumor imaging revealed that after 1 course of treatment 1 patient had partial response (PR), 7had stable disease (SD) and 2had progressive disease. A CTL assay of 10 patients revealed an increase in peptide-specific CTLs in patients with PR and SD, and the clinical responses of those patients were observed. Kaplan‑Meier analysis indicated that patients who had a strong CTL reaction had a tendency to have longer progression‑free survival and overall survival.

経口抗がん剤の調剤に関する実態調査

In this study, a questionnaire survey was conducted among pharmacists to determine the actual dispensing conditions of anti-cancer drugs and problems associated with dispensing drugs, especially after the drugs are taken out of individual packaging. Responses were obtained from 163 pharmacists who had experience in handling oral anticancer drugs. Of these, 76 answered that they had filled oral anti-cancer drug prescriptions, which involved single dose packaging, pulverization of the drug, capsule opening, or preparation of a simple suspension. A total of 107 specific cases involving 26 oral anti-cancer drugs were collected. The drugs were dispensed in accordance with prescriptions in 85 cases (the percentage of prescription questions asked in these cases was 13%) and not in accordance with prescriptions in 16 cases (69%), a prescription was canceled in one case (100%), and details were unknown in 5 cases. Matters noted by the respondents included being careful not to cross-contaminate drugs with other drugs and not to expose dispensers to powdered anti-cancer drugs, which are characteristically easily scattered. The respondents also requested the development of new formulations that do not need special preparation, are easy to dispense and are easy to take for the patients. In conclusion, the following is needed for pharmacists to dispense oral anti-cancer drugs safely and properly: 1) an environment that allows pharmacists to ask physicians about their prescriptions and to cooperate with health professionals by sharing information about anti-cancer regimens; and 2) improvement of the procedures and environment for dispensing such drugs.

Interaction between paliperidone extended release and TS-1&amp;reg;, an oral anticancer drug containing a 5-fluorouracil derivative, in a schizophrenic patient

Until now there has been no information available on drug interaction between paliperidone and TS-1®, an oral anticancer drug containing a 5-fluorouracil derivative. The patient in the case presented here was a 39-year-old man with a 15-year history of schizophrenia. The patient’s usual treatment of 2 mg/day of risperidone was changed to 3 mg/day of paliperidone extended release. He experienced worsening psychotic symptoms after switching from risperidone to paliperidone while he was also receiving TS-1. Retrospective analyses showed plasma concentration of paliperidone was consistently lower during the treatment with TS-1 than without TS-1. This case suggests there is drug interaction between paliperidone extended-release tablets and TS-1.

Induction Therapy with S-1 for Spindle Cell Carcinoma of the External Auditory Canal

We report an unusual case of spindle cell carcinoma of the external auditory canal, which responded well to two weeks’ treatment with the oral fluoropyrimidine anticancer drug S-1 (80 mg/body/day) followed by surgical resection. After the S-1 treatment, the tumor was significantly reduced in size, and a pathological examination only detected small lesions composed of malignant cells. We then conducted a lateral temporal bone resection combined with left modified neck dissection. The patient did not demonstrate any evidence of local recurrence or distant metastasis during the 5-year follow-up period. It is suggested that S-1 played an important role in reducing the size of the tumor to allow radical resection of the tumor with a sufficient surgical margin in the present case and that induction chemotherapy with S-1 prior to surgery might be an effective treatment strategy for controlling spindle cell carcinoma of the ear.

고속액체크로마토그래피 텐덤질량분석기법을 이용한 사람 혈장 내 소라페닙 농도분석법의 개발 및 검정

소라페닙은 멀티카이네즈 억제제로서 신세포암, 전이성 간세포암 환자의 치료에 효과가 입증된 경구용 항암제이다. 이 연구의 목적은 고속액체크로마토그래피 텐덤질량분석기법(LC/MS/MS)을 이용하여 사람 혈장 내 소라페닙의 농도를 측정하는 효율적인 방법을 개발하고 한국식품의약품안전청(KFDA) 기준에 따라 분석법을 검정하는 것이다. 혈장시료(<TEX>$100{\mu}l$</TEX>)에 내부표준물질인 chlorantraniliprole을 첨가한 후 이소프로필알콜과 에틸아세테이트로 구성(1:4, v/v)된 0.1% 포름산 함유 추출용액을 혼합하였다. 원심분리 후 상층액을 취하여 원심감압농축하였다. 잔사를 이동상에 재용해하고 Waters사의 역상 XTerra<TEX>$^{TM}$</TEX> C18 칼럼(입자크기 <TEX>$3.5{\mu}m$</TEX>)을 장착한 고속액체크로마토그래피 장치에 주입하였다. 액체크로마토그래피는 0.1% 포름산과 10 mM 암모늄 포메이트를 함유한 버퍼용액과 메탄올, 아세토나이트릴을 각각 1:6:3으로 혼합한 용액을 이동상으로 사용하였으며 5분 내에 측정을 완료하였다. 분석대상 물질들은 텐덤질량분석기에서 electrospray 양이온 이온화(<TEX>$ES^+$</TEX>) 검출방식으로 확인하였으며 소라페닙은 'm/z 465.2 <TEX>${\rightarrow}$</TEX> 252.5', chlorantraniliprole은 'm/z 484.4 <TEX>${\rightarrow}$</TEX> 286.2'으로 구성한 multiple reaction monitoring 방법을 사용하였다. 검정 결과, 2-5,000 ng/ml의 농도 구간에서 양호한 직선성(<TEX>$r^2$</TEX> > 0.99)과 정확도(90.7-103.9%), 정밀도(10% 이하)를 나타내었다. 새롭게 개발된 LC/MS/MS을 이용한 사람 혈장 내 소라페닙의 농도 측정법은 KFDA 기준을 만족하였으며, 기존의 방법에 비해 민감도가 높은 방법이었다. Sorafenib is a multikinase inhibitor and an oral anticancer drug approved for the treatment of patients with advanced renal cell carcinoma and those with unresectable hepatocellular carcinoma. The purpose of this study was to develop an efficient method of the determination of sorafenib in human plasma using tandem mass spectrometry coupled with liquid chromatography (LC/MS/MS) and validate the method by the guidelines of the Korean Food and Drug Administration (KFDA). Plasma samples (<TEX>$100{\mu}l$</TEX>) were added with chlorantraniliprole as an internal standard and then mixed with the 0.1% formic acid-containing extraction solution composed of isopropyl alcohol and ethyl acetate (1:4, v/v). After centrifugation, the supernatant was concentrated at <TEX>$45^{\circ}C$</TEX> under negative pressure and centrifugal force. The residue was reconstituted with a mobile phase and injected into the HPLC instrument using a reverse phase Waters XTerra<TEX>$^{TM}$</TEX> C18 column (particle size <TEX>$3.5{\mu}m$</TEX>). Liquid chromatography was carried out within the run time of 5 min using a mobile phase composed of buffer (0.1% formic acid and 10 mM ammonium formate), methanol, and acetonitrile (1:6:3, v/v/v). The analytes were monitored by tandem mass spectrometry in the multiple reaction monitoring method programmed to detect sorafenib at 'm/z 465.2 <TEX>${\rightarrow}$</TEX> 252.5' and chlorantraniliprole at 'm/z 484.4 <TEX>${\rightarrow}$</TEX> 286.2' with positive electrospray ionization mode (<TEX>$ES^+$</TEX>). The result showed the proper linearity (<TEX>$r^2$</TEX> > 0.99) over the range of 2,000-5,000 ng/ml with good accuracy (90.7-103.9%) and precision (less than 10%). The newly developed method using LC/MS/MS was validated by the guideline of KFDA and identified as more sensitive compared to the previous methods.

Protective effect of the Japanese traditional medicine juzentaihoto on myelosuppression induced by the anticancer drug TS-1 and identification of a potential biomarker of this effect

BackgroundTS-1 is an oral anticancer drug containing a 5-fluorouracil derivative (Tegafur) that is widely used in Japan for the treatment of cancer, especially gastrointestinal tumors. Frequently, however, TS-1 therapy has to be discontinued because of leukopenia. If it were possible to predict the development of bone marrow suppression before the white blood cell (WBC) count had actually decreased, treatment could be improved by strict dosage control and/or the prophylactic administration of hematopoietic drugs. Juzentaihoto (JTT), a traditional Japanese medicine (Kampo), has been reported to activate hematopoiesis and reduce the side effects associated with chemotherapy and radiotherapy. Here, we 1) evaluate the efficacy of JTT in alleviating myelosuppression induced by TS-1 therapy in mice, and 2) explore biomarkers that reflect both induction by TS-1 and alleviation by JTT of bone marrow suppression using a proteomics approach.MethodsTen mg/kg of TS-1 was administered to Balb/c mice with or without 1 g/kg of oral JTT for 3, 5 and 7 days. WBC count and ratio of CD34+ bone marrow cells (BMCs) were estimated by flow cytometry. Plasma samples were analyzed using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI TOF-MS). A biomarker candidate from SELDI profiling was identified using a combination of cation exchange spin column purification, SDS-PAGE, enzymatic digestion and LC-MS/MS.ResultsAfter administration of TS-1, a significant decrease in WBC count and CD34+ BMC ratio were observed at days 5 and 3, respectively. JTT treatment improved WBC count on day 7 and CD34+ BMC ratio on days 5 and 7. SELDI analysis highlighted three protein peaks that had increased on day 3 after treatment with TS-1 but remained unchanged in mice co-treated with JTT. One of the three peaks, m/z 4223.1, was further investigated and identified as a specific C-terminal fragment of albumin.ConclusionThis study indicates that bone marrow suppression by treatment with TS-1 in mice might be improved by coadministration of JTT. A C-terminal fragment of albumin was identified as a candidate biomarker for predicting TS-1-induced myelosuppression. However, the sensitivity and specificity of the biomarker candidate must be validated in future clinical studies.

Postoperation chemotherapy with S1 and docetaxel in curatively resected gastric cancer of stage III (POST trial).

TPS4142 Background: Complete surgical resections remains the only chance for cure in patients with gastric cancer, but approximately from 40% to 80% of patients still have recurrences and most patients ultimately die from their disease. The recent adjuvant trials in gastric cancer showed significantly improved survival in patients with adjuvant chemotherapy than those with surgery alone. However, further studies need for the effect of adjuvant chemotherapy following D2 dissected gastric cancer patients, especially in advanced gastric cancer. S-1 is an oral anticancer drug, a prodrug of fluorouracil, very effective in gastric cancer. Docetaxel is the first drug that showed survival benefits when added to the two drugs in advanced gastric cancer patients. And docetaxel is also synergistic anti-cancer effect with S-1 in advanced gastric cancer. Base on this background, the aim of this study is to detect a significant increase in 3 –year disease free survival (DFS) of adjuvant chemotherapy with docetaxel and S-1(DS) relative to those with S-1 and cisplatin (SP) in patients with stage III gastric cancer Methods: This study is an open-label, phase 3, randomized controlled trial, multicenter in South Korea. Patients with stage III (AJCC 7th edition) gastric cancer who had had curative D2 gastrectomy is randomly assigned to receive adjuvant chemotherapy of eight 3-week cycles of intravenous docetaxel (35 mg/m2 on day 1 and 8 of each cycle) plus oral S-1 (35 mg/m2 twice daily on days 1 to 14 of each cycle) for 6 months (DS) or chemotherapy of eight 3-week cycles of oral S1 plus intravenous cisplatin (60 mg/m2). After satisfying the screening criteria, patients have been randomized to the SD or SP arm in a 1:1 ratio. The randomization is stratified by institution and stage of disease (IIIA vs. IIIB vs. IIIC). The each stratum has been randomized by using the method of randomly permuted block. The primary endpoint is 3 year DFS, will analyze by intention to treat. A total of 290 patients will be enrolled, 67 patients have been treated to day, with continuing accrual. The trial is registered at ClinicalTrials.gov (NCT01283217).

Dacryoendoscopic observation and incidence of canalicular obstruction/stenosis associated with S-1, an oral anticancer drug

To report dacryoendoscopic observations and the incidence of lacrimal obstruction/stenosis associated with S-1, an oral anticancer drug. Retrospective, nonrandomized clinical trial. A total of 52 patients (41 men, 11 women; age 42-93 years) who were prescribed the anticancer drug S-1 were studied. Patients who suffered eye complaints following S-1 treatment underwent ophthalmic examination, probing and lacrimal irrigation. Patients whose tear meniscus was high or had abnormal lacrimal irrigation were evaluated by dacryoendoscopy. Overall, 5 of 52 S-1-treated patients (9.6%) experienced lacrimal passage stenosis/obstruction. One patient had punctal stenosis, and four patients had canalicular obstruction/stenosis. The onset of epiphora ranged from 2 to 8 months (4.4 ± 2.2 months, mean ± SD) after the initiation of chemotherapy. Patients receiving S-1 treatment should be evaluated for potential lacrimal disorders, particularly canalicular obstruction/stenosis. Dacryoendoscopic observation is effective for the diagnosis of this side effect.