Characterization of nano oxaliplatin prepared by novel Fat Employing Supercritical Nano System, the FESNS^®

Lee, Seung-Jae,Kim, Young-Hoon,Lee, Sang-Heon,Hahn, Mikyoung Informa Healthcare 2012 PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY Vol.17 No.2

<P><I>Background</I>: Oxaliplatin has long been used for the treatment of colorectal cancer via intra-venous infusion. In order to improve patient compliance, a solid dosage form for oral administration of oxaliplatin was prepared as nano-sized particles.</P><P><I>Method</I>: Nano oxaliplatin was prepared employing Fat Employing Supercritical Nano System (FESNS<SUP>®</SUP>) with Supercritical Fluid (SCF) apparatus by using myristyl alcohol as solvent. Morphology of nano oxaliplatin was examined by Scanning Electron Microscopy (SEM), and the particle size and zeta potential were confirmed with Dynamic Light Scattering (DLS). To characterize the nano oxaliplatin particles, solubility rate and in vitro efficacy study (MTS growth inhibition assay) were investigated compared to crude oxaliplatin as reference.</P><P><I>Result</I>: FESNS<SUP>®</SUP> provided reproducible nano oxaliplatin with high manufacturing yield (> 95%). SEM images showed that the particle size distribution of nano oxaliplatin ranged between 20 and 400 nm with the medium particle sizes (<I>d</I><SUB>50</SUB>) of about 164 nm determined by DLS. Pertaining to the long-term stability, no recrystallization of the nano oxaliplatin was observed with negative zeta potential in the state of solution. Nano oxaliplatin was completely dissolved within a couple of minutes in pH 4.0 and pH 6.8 buffer solutions while crude oxaliplatin took a couple of hours to go into solution. In case of MTS growth inhibition assay, the average concentration required to inhibit 50% of cell growth (GI<SUB>50</SUB>) of nano oxaliplatin was decreased by about 45% in comparison to the crude oxaliplatin.</P><P><I>Conclusion</I>: These results lead us to conclude that nano oxaliplatin would have a great potential for the improvement of efficacy and toxicity in human colorectal cancer treatment compared to the crude oxaliplatin.</P>

Antichemosensitizing effect of resveratrol in cotreatment with oxaliplatin in HCT116 colon cancer cell

Dong-Guk Park 대한외과학회 2014 Annals of Surgical Treatment and Research(ASRT) Vol.86 No.2

Purpose: Although oxaliplatin is one of the most widely used chemotherapeutic agents for the treatment of advanced stages of colorectal cancers in clinic, cancer cells often develop oxaliplatin drug resistance. Thus, overcoming oxaliplatin drug resistance is a major issue in the successful treatment for advanced stages of colorectal malignancy. In order to maximize oxaliplatin therapy, we examined whether resveratrol, a natural phytochemical known to have chemopreventive effects on cancers, can have a chemosensitizing effect upon cotreatment with oxaliplatin. Survivin, a small inhibitor of apoptosis protein (IAP), expression is examined using HCT116 colon cancer cells. Methods: In order to examine resveratrol chemosensitizing effect upon oxaliplatin cotreatment, survivin transcripts and protein expression, cell proliferation, and apoptotic responses were evaluated using HCT116 cells. Reverse transcription polymerase chain reaction (RT-PCR), Western blot, crystal violet staining analyses were performed. For survivin specific inhibition, YM155 molecule was used. Results: Although oxaliplatin significantly suppressed survivin transcripts and protein expression level in HCT116 cells, resveratrol cotreatment induced restoration of survivin expression level of both transcripts and protein. Apoptotic induction by oxaliplatin only treatment was nullified upon resveratrol cotreatment. Induction of survivin restoration upon resveratrol cotreatment also occurred when survivin specific inhibitor, YM155, was used. In addition to survivin restoration, resveratrol cotreatment also induced restoration of Bcl-2/caspase-3 expression suppressed by oxaliplatin only treatment. Conclusion: Resveratrol has an antichemosensitizing effect upon cotreatment with oxaliplatin in HCT colon cancer cells. This antichemosensitizing effect of resveratrol can be cell-type specific. However, clinical use of resveratrol cotreatment with oxaliplatin should be approached cautiously.

Oxaliplatin에 의한 안독성의 1예

박한석,김양재,송수정,배정훈,Han Seok Park,MD,Yang Jae Kim,MD,Su Jeong Song,MD,Jeong Hun Bae,MD 대한안과학회 2014 대한안과학회지 Vol.55 No.1

Purpose: To report a case of oxaliplatin (Eloxatin<sup>®)-related ocular toxicity in a patient with advanced stomach cancer. Case summary: A 43-year-old female with advanced stomach cancer experienced visual symptoms during the treatment with oxaliplatin on a XELOX schedule (a combination of oxaliplatin and capecitabine). After 1 cycle of chemotherapy, she complained of blurred vision and visual field defects in both eyes. Visual field tests showed a bilateral concentric field defect and the electroretinogram revealed a marked reduction of responses in both eyes. On the second cycle of chemotherapy, oxaliplatin was discontinued due to suspicious ocular toxicity. Her visual symptoms improved and visual field test showed normal results 1 month after oxaliplatin discontinuation. However, 3 months after oxaliplatin discontinuation, electroretinogram remained abnormal despite the progressive improvement. Conclusions: Platinum-based antineoplastic agents such as oxaliplatin should be administered with caution because oxaliplatin can cause damage to the retinal photoreceptors and the optic nerve. Early detection of ocular toxicity and discontinuation of oxaliplatin therapy could prevent severe and irreversible visual loss. J Korean Ophthalmol Soc 2014;55(1):143-148

전이성 혹은 재발성 위선암에서 Oxaliplatin, Leucovorin, Fluorouracil과 Irinotecan, Leucovorin, Fluorouracil 병합 요법의 효과에 대한 비교 연구

강선형 ( Sun Hyung Kang ),김정일 ( Jeong Il Kim ),문희석 ( Hee Seok Moon ),김석현 ( Seok Hyun Kim ),성재규 ( Jae Kyu Sung ),이병석 ( Byung Seok Lee ),정현용 ( Hyun Yong Jeong ) 대한소화기학회 2010 대한소화기학회지 Vol.55 No.1

목적: 전이성 혹은 재발성 위선암에서 아직까지 타 약제보다 우월한 항암제가 없는 실정에서 oxalipatin과 irinotecan을 각각 leucovorin (LV)과 5-FU와 병합 요법을 시행 후 그 효용성과 부작용을 비교해 보고자 하였다. 대상 및 방법: 2003년 3월부터 2008년 3월까지 대전 지역의 단일 기관에서 수술이 불가능한 전이성 혹은 재발성 위선암으로 진단을 받은 환자 중 계측 가능한 병변을 가진 56명의 환자를 대상으로 의무기록을 바탕으로 후향 연구를 시행하였다. 2주 간격으로 oxaliplatin 100 mg/m2, LV 100 mg/m2를 2시간에 걸쳐 정주한 후 5-FU 2400 mg/m2를 2일에 걸쳐 정주하였고 irinotecan 180 mg/m2, 5-FU 400 mg/m2를 2시간에 걸쳐 정주 후 5-FU 600 mg/m2를 2일간 정주하였고 LV은 이틀 동안 각각 2시간에 걸쳐 20 mg/m2를 정주하였다. 결과: 대상군의 평균 나이는 56.4세였고 남녀비는 36:20으로 남자가 많았다. ECOG 0이 26명, 1이 30명이었다. 계측 가능한 병변은 림프절이 31예, 간이 18예, 난소가 5예였으며 폐와 부신이 각각 1예씩이었다. Oxaliplatin군은 30명, irinotecan군은 26명이었으며 두 군 간의 성별, 연령, ECOG performance 등은 차이가 없었다. Oxaliplatin군에서 CR이 1명(3.3%), PR이 12명(40%)으로 response rate는 43.3%였다. Irinotecan군은 CR이 2명(7.7%), PR이 10명(38.5%)으로 response rate는 46.2%였다. Time to progression은 median값이 oxlaplatin군에서 4개월이 었으며 irinotecan군은 4.5개월이었으나 통계적으로는 의미가 없었다(p=0.994). Overall survival은 각각 8.3개월과 9.7개월로 irinotecan군이 더 길었지만 역시 통계적 의미는 없었다(p=0.784). 1년 후 생존율은 oxaliplatin군이 43.3%, irinotecan군이 34.6%였다. Grade 3/4의 hematologic toxicity는 oxalplatin군에서 neutropenia가 4 case가 발생하였고 irinotecan군은 9 case가 발생하였다. Grade 3의 neuropathy가 oxaliplatin군에서 1예가 발생하였다. 결론: Oxliplatin과 irinotecan의 병합 요법 모두 전이성 및 재발성 위선암에서 안전하고 유용하게 사용할 수 있으며 두 치료의 효용성에는 유의한 차이가 없었다. Background/Aims: We performed retrospective study in order to compare oxaliplatin, leucovorin, and fluorouracil (FOLFOX) versus irinotecan, leucovorin, and fluorouracil (FOLFIRI) in recurred or metastatic gastric adenocarcinoma. Methods: We investigated 56 patients who were diagnosed with recurred or metastatic gastric adenocarcinoma in a single center during march, 2003 to march, 2008. The patients received either FOLFOX or FOLFIRI chemotherapy. Results: There were no significant difference between the Oxaliplatin group (30 patients) and Irinotecan group (26 patients) in sex, age, and ECOG performance (p>0.05). Oxaliplatin group showed 1 case of CR (3.3%) and 12 cases of PR (40%), making the response rate 43.3%. Irinotecan group showed CR in 2 cases (7.7%) and PR in 10 cases (38.5%), making the response rate 46.2%. The median value of time to progression was 4 months in the oxlaplatin group and 4.5 months in the irinotecan group. The overall survival showed no significant difference (p=0.784), with the irinotecan group (9.7 months) being slightly longer than the Oxaliplatin group (8.3 months). Grade 3/4 neutropenia occurred similarly in both groups (4 cases in the oxalplatin group, 9 in the irinotecan group). Conclusions: Both combination treatment can be used safely and effectively in recurred or metastatic gastric adenocarcinoma. (Korean J Gastroenterol 2010;55:26-32)

Change in Expression of Survivin Caused by Using Oxaliplatin in HCT116 Colon Cancer Cells

손원준,이정원,박동국 대한대장항문학회 2010 Annals of Coloproctolgy Vol.26 No.4

Purpose: Oxaliplatin is a third-generation platinum compound, and it has no nephrotoxicity and has reduced bone marrow toxicity. Cancer cells that are resistant to cisplatin are sensitive to oxaliplatin. Oxaliplatin is used widely for the treatment of colon cancers. Recently, oxaliplatin was reported to inhibit the expression of survivin, which protects cell apoptosis. However, there are no reports on the expressions of survivin variants and the changes in intracellular localization of survivin in cancer cells. We studied the expression of survivin caused by oxaliplatin in HCT116 colon cancer cells, and we observed the localization of survivin in the mitotic phase. Methods: We treated the HCT116 colon cancer cells with 2.0 μM of oxaliplatin, and we studied the expressions of survivin protein, and survivin mRNA variants, as well as the changes in intracellular localization, by using the Western blot method,RT-PCR, immunocytochemistry, and flowcytometry. Results: Oxaliplatin inhibits the expression of the survivin protein and survivin mRNA in HCT116 colon cancer cells. The expression of the survivin-2B variants, which have no antiapoptotic activity but control cell mitosis by localization on a microtubule, is reduced continuously 2 days after treatment with oxaliplatin. In immunocytochemistry, expression of survivin in the cytoplasm is reduced and especially is not expressed in microtubules and contractile rings. Conclusion: One of the mechanisms of oxaliplatin is to inhibit the expression of and to change the localization of survivin. Based on these results, we suggest that changes in the expression of survivin variants and in their localization are two effects of oxaliplatin.

5-Fluorouracil, Leucovorin과 병용 투여된 Oxaliplatin의 Dose Intensity가 재발된 전이성 대장암 치료에 미치는 영향

정경주,최승기,오정미,Jeong, Kyong-Ju,Choi, Seung-Ki,Oh, Jung-Mi 한국임상약학회 2004 한국임상약학회지 Vol.14 No.1

Studies of oxaliplatin, 5-fluorouracil and leucovorin in pretreated metastatic colorectal cancer showed that oxaliplatin dose intensity is important prognostic factor for objective response rates and progression-free-survival (PFS). To evaluate response rates, PFS and toxicity according to oxaliplatin dose intensity, we retrospectively analyzed data from patients with metastatic colorectal cancer received oxaliplatin,5-fluorouracil, leucovorin regimens. Sixty-three patients were reviewed in this study, 42 patients received low dose intensity oxaliplatin (LDI: $\leq85\;mg/m^2/2wks$) and 21 patients high dose intensity oxaliplatin (HDI: $>85\;mg/m^2/2wks$). Objective responses occurred in 10 $(47.7\%)$ HDI patients and 9 $(21.4\%)$ LDI patients (p = 0.014). Median PFS was 24.7 weeks in HDI group, with $45.1\%$ of HDI patients progression free at 6 months, and 20.5 weeks in LDI group, with $33.5\%$ of LDI patients progression free at 6 months (p = 0.344). Increased oxaliplatin dose intensity was not associated with neutropenia, thrombocytopenia, neuropathy, nausea and vomiting. This study showed that oxaliplatin dose intensification significantly improves objective response rate in pretreated metastatic colorectal cancer without increasing severe toxicity.

Oxaliplatin-Induced Chronic Peripheral Neurotoxicity:A Prospective Analysis in Patients with Colorectal Cancer

백경기,이지연,박세훈,박준오,박영석,임호영,강원기,조용범,윤성현,김희철,이우용,전호경 대한암학회 2010 Cancer Research and Treatment Vol.42 No.4

Purpose Oxaliplatin-induced chronic peripheral neurotoxicity (OXCPN) manifests as a loss of sensation and dysesthesia in the distal extremities, which may impair daily activities and increase in incidence with the amount of oxaliplatin delivered. The variation in the reported incidence and severity of OXCPN may be a consequence of differences in the baseline characteristics of patients. Materials and Methods This was a prospective study (ClinicalTrials.gov, NCT00977717) in which OXCPN was recorded for all consecutive colon cancer patients treated at Samsung Medical Center (Seoul, Korea) with oxaliplatin-based combination chemotherapy. The primary endpoint was the incidence of severe OXCPN (grade 2 lasting for >7 days, or grade 3). The association of severe OXCPN and pretreatment parameters was evaluated using a multivariate regression model. Results Between Jan 2008 and Feb 2010, 100 patients treated with adjuvant folinic acid/fluorouracil plus oxaliplatin (FOLFOX) and 266 patients treated with capecitabine plus oxaliplatin (XELOX) or FOLFOX for advanced disease were registered into our study. The median cumulative dose of oxaliplatin was 796 mg/m2 (range, 85 to 1,583 mg/m2). Severe OXCPN was observed in 126 (34%) patients. Overall, 43 patients discontinued chemotherapy due to toxicity: 23 without severe OXCPN and 20 with severe OXCPN. In univariate analysis, severe OXCPN was frequently observed in patients with age ≥55 years (p<0.01), stage II or III (p<0.01), adjuvant setting (p=0.01), FOLFOX (p<0.01), performance status of 0 (p=0.02), and those with no prior chemotherapy (p<0.01). In a multivariate regression model, the number of chemotherapy cycles and the cumulative oxaliplatin dose were not associated with the development of severe OXCPN. Conclusion We failed to find a significant association between patient characteristics at baseline and the development of severe OXCPN after oxaliplatin-based combination chemotherapy. Pharmacogenomic profiling using genome-wide association study in these patients is underway.

Inhibition of oxaliplatin-induced neurotoxicity by silymarin through increased expression of brain-derived neurotrophic factor and inhibition of p38-MAPK

Ji-Young Choi,Hyeon Gyu Yi,Chang-Shin Park,Dong Wun Shin,Ju-Hee Kang 대한독성 유전단백체 학회 2019 Molecular & cellular toxicology Vol.15 No.2

Backgrounds: Oxaliplatin is a chemotherapeutic agent that induces neuropathy through unknown mechanisms and therefore, its pharmacological performance is limited. Silymarin, a well-known hepatoprotective natural flavonoid mixture, has neuroprotective effects against certain neurodegenerative or neurotoxic stimuli. Methods: We tested whether silymarin protects against oxaliplatin-induced neurotoxicity by using a neuronal cell culture system. Using differentiated SH-SY5Y cells, effects of silymarin on the oxaliplatin-mediated cytotoxicity for cell viability, oxidative stress and BDNF expression. Results: Treatment of neuronal cells with oxaliplatin decreased cell viability, which was accompanied by increase in levels of the apoptotic marker cleaved poly-( ADP-ribose) polymerase (PARP) and malondialdehyde (MDA), a marker of lipid peroxidation. We found that oxaliplatin-induced cell death was partially mediated by p38-MAPK activation, which was significantly inhibited by silymarin. Silymarin slightly but not significantly inhibited oxaliplatin-induced oxidative stress. It also upregulated brain-derived neurotrophic factor (BDNF) expression and increased calcium-calmodulin kinase II and CREB activities. The observation of cell morphology revealed that silymarin induced dendritic outgrowth, which was validated by the increased expression of β-III tubulin protein. Furthermore, we observed that oxaliplatin-induced loss of dendritic outgrowth and BDNF downregulation were partially blocked by silymarin. Conclusion: Our results suggested that oxaliplatin-induced neuropathy may be caused by combined mechanisms of increased oxidative stress, p38 MAPK-mediated apoptosis, and reduction of BDNF expression. All these changes were significantly inhibited by silymarin.

Effects of Analgecine on Oxaliplatin-Induced Neurotoxicity in Patients with Gastrointestinal Cancer

Liu, Meng-Yan,Huang, Xin-En Asian Pacific Journal of Cancer Prevention 2015 Asian Pacific journal of cancer prevention Vol.16 No.10

Background: As the third generation of platinum-based antineoplastic agent aginst gastrointestinal cancer, oxaliplatin is considered to be associated with severe sensory neurotoxicity. Acorrding to previous studies, vitaminE, intravenous Ca/Mg and glutamine may partly reduce the incidence and severity of oxaliplatin-induced neurotoxicity. The aim of this study was to investigate the safety and efficacy of analgecine for preventing oxaliplatin-induced neurotoxicity in the patients with gastrointestinal tumors. Method: In this study, patients undergoing oxaliplatin-based chemotherapy were assigned to analgecine (experimental) group or control group. Analgecine 6ml was administered once a day for seven days from the day of oxaliplatin treatment. The National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE; version 3) was used to evaluate oxaliplatin-induced neurotoxicity. The incidence rates and grade of neurotoxicity of patients were assessed before and during (after four and eight cycles) treatment. Results: Totally, 82 patients were enrolled in this study, 42 in experimental group and 40 in control group. The occurrence of each grade neurotoxicity in the experimental group was significantly lower than that in control group. The overall occurrence rate was 31% vs 55% (P=0.043) after 4 cycles and 52% vs 75% (P=0.050) after 8 cycles. Conclusion: Analgecine appears could be effective in reducing oxaliplatin-induced neurotoxicity and be applicated for patients with gastrointestinal tumors who would be treated with oxaliplatin-based chemotherapy.

Ursodeoxycholic acid switches oxaliplatin-induced necrosis to apoptosis by inhibiting reactive oxygen species production and activating p53-caspase 8 pathway in HepG2 hepatocellular carcinoma

Lim, Sung-Chul,Choi, Jeong Eun,Kang, Ho Sung,SI, Han Wiley Subscription Services, Inc., A Wiley Company 2010 International journal of cancer: Journal internati Vol.126 No.7

<P>Hepatocellular carcinoma (HCC) is resistant to chemotherapy. Recently, however, several oxaliplatin-based combinatorial treatments have shown a promising anti-tumor activity in patients with HCC. Presently, we demonstrate that oxaliplatin triggers necrosis more than apoptosis in HepG2, SK-Hep1, SNU-423 and Hep3B HCC cells, while mainly inducing apoptosis in HCT116 and HT29 colon cancer cells. Interestingly, ursodeoxycholic acid (UDCA), a less hydrophobic bile acid that can suppress carcinogenesis, shifted oxaliplatin-induced necrosis to apoptosis in HepG2 cells. The same effect was produced by hydrophilic bile acids (tauroursodeoxycholic acid and taurohyodeoxycholic acid), but not by highly hydrophobic bile acids (deoxycholic acid and chenodeoxycholic acid). UDCA also triggered the necrosis-to-apoptosis switch when cotreated with other platinum-based chemotherapeutic drugs including cisplatin and carboplatin, suggesting that the cell death mode switching effect of UDCA is a general phenomenon when combined with platinum drugs. Oxaliplatin produced high level of reactive oxygen species (ROS) in HepG2 cells and UDCA significantly reduced oxaliplatin-induced ROS generation. In addition, N-acetyl-L-cysteine and the superoxide scavengers butylated hydroxyanisole and dihydroxybenzene-3,5-disulfonic acid attenuated necrosis, indicating a critical role(s) of ROS in occurrence of necrotic death. Apoptosis induced by combined treatment appeared to be mediated by p53-caspase 8-caspase 3 pathway. In conclusion, UDCA switches oxaliplatin-induced necrosis to apoptosis via inhibition of ROS production and activation of the p53-caspase 8 pathway in HepG2 cells. As necrosis and subsequent inflammation are implicated in tumor progression and malignancy, our results imply a potential improved efficacy of UDCA-combined chemotherapy in HCC by reducing inflammatory responses that may be triggered by oxaliplatin.</P>