Cancer Research and Treatment

Case Report

A Case of 5-Fluorouracil Induced Encephalopathy: Kyung A Kwon, Hyuk-Chan Kwon, Min Chan Kim, Sung-Hyun Kim, Sung Yong Oh, Suee Lee, Hyo-Jin Kim; Cancer Res Treat. 2010;42(2):118-120. Published online June 30, 2010; DOI: https://doi.org/10.4143/crt.2010.42.2.118

Patients with reduced dihydropyrimidine dehydrogenase (DPD) activity are at risk for experiencing serious adverse effects following 5-fluorouracil (5-FU) based chemotherapy. Neurotoxicity is considered an extremely rare side effect of 5-FU. We report here on an unusual case of 5-FU induced encephalopathy. A 38-year-old woman with advanced gastric carcinoma was treated with adjuvant chemotherapy that consisted of infused 5-FU (1,000 mg/m²) for 5 days and cisplatin (60 mg/m²) on day 1 following total gastrectomy. Nineteen days after starting chemotherapy, the patient displayed a sudden onset of slurred speech, confusion, cognitive disturbances and paranoia. A magnetic resonance image (MRI) of the brain showed no structural abnormalities, and the other laboratory tests provided no explanations for her symptoms, other than a slightly elevated ammonia level. The patient was treated with a lactulose retention enema and thiamine infusion, the 5-FU was halted and her symptoms then recovered after 7 days.

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International Journal of Molecular Sciences.2025; 26(3): 1186. CrossRef
5-Fluorouracil-induced Reversible Encephalopathy
T. M. Varun, P. Prasun, Dipa Amte
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Four decades of chemotherapy-induced cognitive dysfunction: comprehensive review of clinical, animal and in vitro studies, and insights of key initiating events
Ana Dias-Carvalho, Mariana Ferreira, Rita Ferreira, Maria de Lourdes Bastos, Susana Isabel Sá, João Paulo Capela, Félix Carvalho, Vera Marisa Costa
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Chemotherapy-Induced Acute Reversible Toxic Leukoencephalopathy
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Hyperammonemic encephalopathy associated with 5-fluorouracil in a patient with previous orthotopic liver transplantation
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5-Fluorouracil rechallenge after 5-fluorouracil-induced hyperammonemic encephalopathy
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Prevention of 5-fluorouracil-induced early severe toxicity by pre-therapeutic dihydropyrimidine dehydrogenase deficiency screening: Assessment of a multiparametric approach
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5-FU-induced neurotoxicity in cancer patients with profound DPD deficiency syndrome: a report of two cases
Pierre-Yves Cordier, André Nau, Joseph Ciccolini, Manuela Oliver, Cédric Mercier, Bruno Lacarelle, Eric Peytel
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Original Articles

A Phase II Trial of Haptaplatin/5-FU and Leucovorin for Advanced Stomach Cancer: Won Sup Lee, Gyeong-Won Lee, Hwal Woong Kim, Ok-Jae Lee, Young-Joon Lee, Gyung Hyuck Ko, Jong-Seok Lee, Joung Soon Jang, Woo Song Ha; Cancer Res Treat. 2005;37(4):208-211. Published online August 31, 2005; DOI: https://doi.org/10.4143/crt.2005.37.4.208

Abstract PDF PubReader ePub

Purpose

Heptaplatin (SKI-2053 R) is a new platinum analogue, with a better toxicity profile than cisplatin, and has antitumor activity even in cisplatin resistant cell lines. 5-fluoruracil (5-FU) has shown synergy with platinum compounds. This phase II trial was designed to determine the efficacy and toxicities of heptaplatin/ 5-FU (5-fluorouracil) for treating stomach cancer.

Materials and Methods

Thirty-two patients with advanced, measurable gastric adenocarcinomas were enrolled in this trial. The treatment consisted of heptaplatin, 400 mg/m²/day (1 hour IV infusion), on day 1 and 5-FU, 800 mg/m²/day (12 hours IV infusion), on days 1 to 5. The cycles were repeated every 3 weeks.

Results

Of the 26 evaluable patients, 9 had partial responses and 1a complete response (overall response rate, 38%; 95% confidence interval, 19~57%). The median response duration was 23 weeks (range: 4~60 weeks). The median time to progression was 26 weeks (range: 3~68 weeks). The grades III-IV toxicities were mostly hematological toxicities: leucopenia was observed in 11 patients (35%) and thrombocytopenia 4 (13%). No definite neuropathy was observed. Grade I-II nephropathy was also noted: grade I high BUN/creatinine levels occurred in 5 patients (16%), grade II proteinuria 2 (6%), grade I proteinuria 5 (16%). Neutropenic fever developed in 5 patients (16%) and 1 died of pneumonia in a neutropenic state.

Conclusion

This study suggests that the regimen of Heptaplatin/5-FU should be effective and have a favorable toxicity profile for the patients suffering with advanced stomach cancer.

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Cisplatin Resistance in Cancer Therapy: Causes and Overcoming Strategies
S. Shruthi, K. Bhasker Shenoy
ChemistrySelect.2024;[Epub] CrossRef
Application of Approved Cisplatin Derivatives in Combination Therapy against Different Cancer Diseases
Dobrina Tsvetkova, Stefka Ivanova
Molecules.2022; 27(8): 2466. CrossRef
Synthesis of novel heptaplatin derivatives and evaluation of their ability to inhibit proliferation of cancer cell lines
W. Xu, D. C. Wang
Russian Journal of General Chemistry.2016; 86(4): 939. CrossRef
The extract of Paris polyphylla exerts apoptotic induction and synergic antiproliferative effect with anticancer drugs in SMMC-7721 human liver cancer cells
Jing Sun, Bao-rui Liu, Jia Wei, Xiao-ping Qian, Li-xia Yu, Ren-hua Guo, Hua Shen, Tong-shan Wang, Yong-qian Shu
Biomedicine & Preventive Nutrition.2011; 1(3): 186. CrossRef
The status of platinum anticancer drugs in the clinic and in clinical trials
Nial J. Wheate, Shonagh Walker, Gemma E. Craig, Rabbab Oun
Dalton Transactions.2010; 39(35): 8113. CrossRef
Prognostic value of expression of ERCC1, thymidylate synthase, and glutathione S-transferase P1 for 5-fluorouracil/oxaliplatin chemotherapy in advanced gastric cancer
H.-C. Kwon, M.S. Roh, S.Y. Oh, S.-H. Kim, M.C. Kim, J.-S. Kim, H.-J. Kim
Annals of Oncology.2007; 18(3): 504. CrossRef

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Oxaliplatin with Biweekly, Low Dose Leucovorin and Bolus and Continuous Infusion 5-fluorouracil (Modified FOLFOX 4) as First-line Therapy for Patients with Metastatic Colorectal Cancer: Hyuk-Chan Kwon, Kyoung Tae Kim, Shin Ae Lee, Jong-Sung Park, Sung-Hyun Kim, Jae-Seok Kim, Hyo Jin Kim; Cancer Res Treat. 2004;36(2):115-120. Published online April 30, 2004; DOI: https://doi.org/10.4143/crt.2004.36.2.115

Abstract PDF PubReader ePub

Purpose

To determine the activity and toxicities of low dose leucovorin (LV) plus fluorouracil (5-FU) regimen, combined with oxaliplatin every two weeks (modified FOLFOX 4), as a first-line therapy for patients with metastatic colorectal cancer.

Materials and Methods

Between March 2001 and August 2003, fifty-five patients were enrolled in this study. Patients were treated with oxaliplatin 85 mg/m² as a 2-hour infusion at days 1 plus LV 20 mg/m² over 10 minutes, followed by 5-FU bolusa 400 mg/m² bolus and 22 hour continuous infusion of 600 mg/m² 5-FU at day 1~2. This treatment was repeated in 2 week intervals.

Results

The objective response rate was 40% on an intent-to-treatment analysis. Three patients (6%) demonstrated a complete response and nineteen patients (38%) showeda partial response. Sixteen patients (32%) showed a stable disease and eleven patients (22%) progressed during the course of the treatment. The median time to progression and overall survival time wereas 6.6 months (95% CI: 4.98~8.02 months) and the median overall survival time was 17.0 months (95% CI: 9.15~24.85 months) from the start of the chemotherapy, respectively. A total of 275 cycles were analyzed for toxicity. Major hematologic toxicities included grade 1~2 anemia (23.5%), neutropenia (25.3%) and thrombocytopenia (10.6%). There were only 2 cycles of neutropenic fever. The most common non-hematologic toxicities were grade 1~2 nausea/vomiting (10.9%), diarrhea (9.1%) and grade 1 neuropathy (18.0%). There was no treatment related death.

Conclusion

The modified folfox 4 regimen is safe and effective regimen as a first-line therapy in advanced colorectal cancer patients.

Citations

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A Phase II Study of Modified FOLFOX4 for Colorectal Cancer Patients with Peritoneal Carcinomatosis
Dong Hyun Lee, Sung Yong Oh, Yu Rim Lee, Seok Jae Huh, Hyun Hwa Yoon, Sung Hyun Kim, Suee Lee, Ji Hyun Lee, Young Kim, Hyo-Jin Kim, Hyuk-Chan Kwon
Cancer Research and Treatment.2011; 43(4): 225. CrossRef
Outpatient-basis Chemotherapy of Oxaliplatin, 5-fluorouracil, and Leucovorin as First-line Treatment for Patients with Metastatic or Recurrent Colorectal Cancer
Joon Ho Moon, Jong Gwang Kim, Sang Kyun Sohn, Jin Ho Baek, Yoon Young Cho, Yee Soo Chae, Byung Min Ahn, Shi Nae Kim, Soo Jung Lee, In Taek Lee, Gyu Seog Choi, Soo Han Jun
Journal of Korean Medical Science.2007; 22(3): 400. CrossRef
Oxaliplatin/5-FU without Leucovorin Chemotherapy in Metastatic Colorectal Cancer
Byoung Yong Shim, Kang Moon Lee, Hyeon-Min Cho, Hyun Jin Kim, Hong Joo Cho, Jinmo Yang, Jun-Gi Kim, Hoon-Kyo Kim
Cancer Research and Treatment.2005; 37(4): 212. CrossRef
Combination Chemotherapy of Oxaliplatin, 5-Fluorouracil and Low Dose Leucovorin in Patients with Advanced Colorectal Cancer
Yoon Mi Shin, Hae Suk Han, Seong Woo Lim, Byung Chul Kim, Kyung Suck Cheoi, Young Ook Eum, Seung Taek Kim, Ki Hyeong Lee
Cancer Research and Treatment.2005; 37(5): 284. CrossRef
Oxaliplatin with Biweekly Low Dose Leucovorin and Bolus and Continuous Infusion of 5-fluorouracil (Modified FOLFOX 4) as a Salvage Therapy for Patients w ith Advanced G astric Cancer
Sung-Hwan Suh, Hyuk-Chan Kwon, Ji-Hoon Jo, Young-Rak Cho, Bong-Gun Seo, Dong-Mee Lee, Sung-Hyun Kim, Jae-Seok Kim, Hyo-Jin Kim
Cancer Research and Treatment.2005; 37(5): 279. CrossRef
Oxaliplatin: Is It a New Standard Weapon for Colorectal Cancer?
Si-Young Kim
Cancer Research and Treatment.2004; 36(2): 91. CrossRef

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Infusional 5-Fluorouracil, Leucovorin and Docetaxel in Advanced Gastric Cancer: Yong Tai Kim, Joo Hyuk Sohn, So Hun Kim, Sun Young Rha, Chul Kim, Jae Kyung Roh, Byung Soo Kim, Woo Ick Jang, Hyun Cheol Chung; Cancer Res Treat. 2003;35(2):123-129. Published online April 30, 2003; DOI: https://doi.org/10.4143/crt.2003.35.2.123

Abstract PDF

PURPOSE
This study was performed to estimate the response rate and toxicity of a combination chemotherapy, which included infusional 5-Fluorouracil, Leucovorin and Docetaxel in the treatment of patients with an advanced gastric carcinoma. MATERIALS AND METHODS: Twenty two advanced gastric cancer patients, with a bidimensionally measurable or an evaluable disease, were enrolled in this study. The patients received a 5-fluorouracil 1, 000 mg/m2 intravenous (IV) 24 hour infusion (Day 1~3), leucovorin 20 mg/m2 (Day 1~3) and docetaxel 75 mg/m2 intravenously (Day 2) every 3 weeks. RESULTS: The overall response rate was 45.0%. The median duration of response was 10.0 weeks (range: 4~24), the median time to response was 8 weeks (range: 8~20) the median time to progression was 30.0 weeks (95% CI: 16.3~43.2) and the median overall survival duration was 36.0 weeks (95% CI: 1.7~70.2). The median cumulative dose of 5-fluorouracil were 316.2 mg/m2/week and docetaxel was 23.9 mg/m2/week. WHO grade III, IV neutropenia, thromocytopenia and anemia occurred in 50.0%, 4.5% and 4.5% of patients, respectively. There were no occurrence of WHO grade III and IV nausea, vomiting, mucositis, conspitation, diarrhea, or neurotoxicity. CONCLUSION: This chemotherapy regimen, including infusional 5-fluorouracil, leucovorin and docetaxel was an active agent against advanced gastric cancer patients, especially for previous chemotherapy naive patients.

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The Efficacy of Docetaxel and Cisplatin Combination Chemotherapy for the Treatment of Advanced Gastric Cancer after Failing to 5-Fluorouracil Based Chemotherapy
Sang-Joon Shin, Min-Kyoung Kim, Kyung-Hee Lee, Myung-Soo Hyun, Sang Woon Kim, Sun Kyo Song, Sung-Hwa Bae, Hun-Mo Ryoo
Cancer Research and Treatment.2004; 36(6): 367. CrossRef

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Salvage Treatment for Advanced Gastric Cancer Using FEP (5-FU, Etoposide, Cisplatin) Combination Chemotherapy: Je Hyuk Chung, Yee Zee Bae, Sung Hyun Kim, Chang Hoon Moon, Jun Young Chung, Hyuk Chan Kwon, Jae Seok Kim, Hyo Jin Kim; Cancer Res Treat. 2002;34(5):382-387. Published online October 31, 2002; DOI: https://doi.org/10.4143/crt.2002.34.5.382

Abstract PDF

PURPOSE
There is no effective treatment for patients with advanced gastric cancer having failed to respond to first line chemotherapy. The aim of this study was to evaluate the therapeutic activity, and safety, of a FEP regimen in patients with a recurrence of, or metastatic, gastric cancer that had been unresponsive to primary chemotherapy.
MATERIALS AND METHODS
Recurred or metastatic gastric cancer patients that did not respond to a 5-fluorouracil based regimen were entered into this trial. The patients were treated with FEP (5-FU, etoposide and cisplatin) as salvage chemotherapy. The treatment regimen was 5-FU (900 mg/m2/day) by continuous infusion for 3 days, etoposide (90 mg/m2/day) on days 1, 2 and 3, and cisplatin (60 mg/m2/day) on day 2. This treatment was repeated every 3 weeks.
RESULTS
Between December 1997 and October 2001, 28 patients were enrolled to the study. The response rate was 32.1% (95% CI 15.5~57.8%). The median times to progression and survival duration were 23~33 weeks, respectively. Among a total of 187 cycles of chemotherapy, the grade 3 and 4 hematological toxicities were leukopenia (6.4%), thrombocytopenia (1.6%), and grade 3 non-hematological side effects of nausea/vomiting (17.9%).
CONCLUSION
FEP combination chemotherapy seems to be an effective treatment regimen for gastric cancer as salvage chemotherapy. To confirm these results, large scale of clinical trials will be required.

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Anticancer Effect of a Novel Octahydropyrazino[2,1-a:5,4-a′]diisoquinoline Derivative and Its Synergistic Action with Nigella sativa in Human Gastric Cancer Cells
Anna Czajkowska, Agnieszka Gornowicz, Natalia Pawłowska, Robert Czarnomysy, Jolanta Nazaruk, Wojciech Szymanowski, Anna Bielawska, Krzysztof Bielawski
BioMed Research International.2017; 2017: 1. CrossRef
The Efficacy of Docetaxel and Cisplatin Combination Chemotherapy for the Treatment of Advanced Gastric Cancer after Failing to 5-Fluorouracil Based Chemotherapy
Sang-Joon Shin, Min-Kyoung Kim, Kyung-Hee Lee, Myung-Soo Hyun, Sang Woon Kim, Sun Kyo Song, Sung-Hwa Bae, Hun-Mo Ryoo
Cancer Research and Treatment.2004; 36(6): 367. CrossRef

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Antitumor Activity of Oxaliplatin, 5-FU and Paclitaxel Given Alone or in Combination with ZD1839 in Human Gastric Carcinoma Cells in vitro: Ji Hyun Jang, Sang Hak Lee, Jin Hyoung Kang, Hee Sik Sun, Kazuto Nishio, Nagahiro Saijo, Hyo Jeong Kuh; Cancer Res Treat. 2002;34(5):372-381. Published online October 31, 2002; DOI: https://doi.org/10.4143/crt.2002.34.5.372

Abstract PDF

PURPOSE
Oxaliplatin (LOHP), 5-FU, and paclitaxel (PTX) are considered highly active against advanced gastric carcinomas, and the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, ZD1839 is considered as a good candidate for the treatment of gastric cancers when given alone or in combination with cytotoxic agents. The present study evaluated the antitumor effects of these agents in SNU-1 human gastric cancer cells either alone or when given as a doublet (i.e., as a cytotoxic-cytostatic combination).
MATERIALS AND METHODS
We selected SNU-1 cells that showed DNA mismatch repair (MMR) deficiency and EGFR overexpression. Growth inhibition was measured by MTT and by direct cell counting and cell cycle distribution by flow cytometry. The combination index (CI) was used to describe synergistic interaction.
RESULTS
The four drugs showed IC50s ranging from 1.81 nM to 13.2microM. MTT assay appeared to underestimate the cytotoxicity of PTX, which was attributed to a significant resistant fraction (32%). LOHP and PTX induced G2/M arrest, 5-FU increased in S phase, and ZD1839 in-creased in G1 in a concentration dependent manner. PTX ZD1839 showed the greatest synergism and LOHP ZD1839 showed a similar result. The cell cycle effect of PTX was potentiated by the coadministration of ZD1839. A previously developed cytostatic TPi model was used to assess the contribution of cell cycle arrest to overall growth inhibition, and 64% and 80% of the overall growth inhibition was attributed to cell cycle arrest for LOHP and PTX, when exposed to 7.55microM and 10 nM for 72 hr, respectively.
CONCLUSION
This study demonstrates the antitumor activity and significant cell cycle arrest effect of ZD1839 against human gastric carcinoma cells and its synergistic interaction with LOHP and PTX. These results provide a preclinical rationale for the clinical development of ZD1839 and its use in combination with LOHP or PTX against human gastric cancers that express EGFR.

Citations

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An efficient and flexible framework for inferring global sensitivity of agent-based model parameters
Daniel R. Bergman, Trachette Jackson, Harsh Vardhan Jain, Kerri-Ann Norton, Nicholas Geard
PLOS Computational Biology.2025; 21(9): e1013427. CrossRef
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Marisa C. Eisenberg, Harsh V. Jain
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A Phase II Study of Oxaliplatin Combined with 5-Fluorouracil and Leucovorin (Mayo Clinic Regimen) in 5-Fluorouracil Refractory Colorectal Cancer: Yee Zee Bae, Jae Hyuk Jung, Chang Hoon Moon, Seong Hyun Kim, Hyuk Chan Kwon, Jae Seok Kim, Hyo Jin Kim; Cancer Res Treat. 2002;34(3):218-222. Published online June 30, 2002; DOI: https://doi.org/10.4143/crt.2002.34.3.218

Abstract PDF

PURPOSE
There are few therapeutic options in patients with colorectal cancer that have progressed or recurred following 5-fluorouracil (5-FU) based therapy. We evaluated the efficacy and toxicity of oxaliplatin, 5-FU, leucovorin (Mayo clinic regimen) in 5-FU pretreated advanced colorectal cancer patients. MATERIALS AND METGODS: Twenty-eight patients were enrolled in this study between January 1999 and May 2001. Patients were treated with oxaliplatin 150 mg/m2 on day 1 as a 2-hr infusion and 5-FU 425 mg/m2, leucovorin 20 mg/m2, bolus for 5 days. Treatment courses were repeated in 4-week intervals.
RESULTS
The objective response rate was 25% for 28 assessable patients, all cases registered a partial response. Eleven patients (39%) demonstrated stable disease, and ten (36%) progressed. The median response duration was 5.5 months, and the median time to progression was 6.3 months. The median overall survival time was 13.5 months from the start of the chemotherapy. From the 120 cycles analyzed, grade 3,4 hematologic toxicities included neutropenia: 1.6%, and thrombocytopenia: 1.6%. The frequent grade 3.4 non-hematologic adverse reactions were nausea/vomiting (25.0%), diarrhea (14.3%), stomititis (3.6%), and neuropathy (3.6%). There were no treatment-related deaths.
CONCLUSION
This phase II study had relatively higher toxicity than previous studies, and did not show an increased significant response rate. These high levels of toxicity suggest that the study treatment combination of oxaliplatin with a full dose Mayo clinic regimen arm is no feasible. Therefore, this regimen will be discontinued and a safer regimen will be adopted.

Citations

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Effect of Betulinic Acid on Anticancer Drug‐Resistant Colon Cancer Cells
Gwon‐Ryul Jung, Kyung‐Jong Kim, Cheol‐Hee Choi, Tae‐Beum Lee, Song Iy Han, Hyo‐Kyung Han, Sung‐Chul Lim
Basic & Clinical Pharmacology & Toxicology.2007; 101(4): 277. CrossRef
Oxaliplatin/5-FU without Leucovorin Chemotherapy in Metastatic Colorectal Cancer
Byoung Yong Shim, Kang Moon Lee, Hyeon-Min Cho, Hyun Jin Kim, Hong Joo Cho, Jinmo Yang, Jun-Gi Kim, Hoon-Kyo Kim
Cancer Research and Treatment.2005; 37(4): 212. CrossRef
The Efficacy of a Modified Chronomodulated Infusion of Oxaliplatin, 5-Fluorouracil and Leucovorin in Advanced Colorectal Cancer (Preliminary Data)
Ji Young Park, Si-Young Kim, Jae Jin Lee, Hwi Joong Yoon, Kyung Sam Cho
Cancer Research and Treatment.2004; 36(3): 199. CrossRef
Oxaliplatin with Biweekly, Low Dose Leucovorin and Bolus and Continuous Infusion 5-fluorouracil (Modified FOLFOX 4) as First-line Therapy for Patients with Metastatic Colorectal Cancer
Hyuk-Chan Kwon, Kyoung Tae Kim, Shin Ae Lee, Jong-Sung Park, Sung-Hyun Kim, Jae-Seok Kim, Hyo Jin Kim
Cancer Research and Treatment.2004; 36(2): 115. CrossRef

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Concurrent Chemoradiotherapy in Locally Advanced Carcinoma of the Uterine Cervix Preliminary Results of Phases III Prospective Randomized Trial: Young Seok Kim, Eun Kyung Choi, Jong Hoon Kim, Seung Do Ahn, Sang Wook Lee, Jong Hyeok Kim, Yong Man Kim, Young Tak Kim, Jung Eun Mok, Joo Hyun Nam; Cancer Res Treat. 2002;34(3):191-197. Published online June 30, 2002; DOI: https://doi.org/10.4143/crt.2002.34.3.191

Abstract PDF: PURPOSE
A prospective, randomized phase III, clinical trial was performed to assess treatment related acute toxicity, early response and survival difference, between a monthly 5-FU cisplatin, and a weekly cisplatin group alone, for concurrent chemoradiotherapy in the locally advanced uterine cervical carcinoma patients. MATERIALS AND METGODS: Between March 1998 and March 2000, 35 patients, with locally advanced (FIGO stage IIB to IVA) cervical carcinoma, were studied, but 5 patients were excluded inform the analysis due to their refusal of treatment. The patients were randomly assigned to 'monthly 5-FU cisplatin' (arm I), or 'weekly cisplatin' (arm II), groups. The patients of arm I received 5-FU cisplatin (5-FU 1,000 mg/m2/day cisplatin 20 mg/m2/day, IV continuous infusion, for 5 days, 3 cycles with 4-week intervals) with radiation therapy. Those of arm II received only cisplatin (cisplatin 30 mg/m2/day, IV bolus, 6 cycles with 1-week intervals) with radiation therapy. The radiation therapy consisted of external beam irradiation of 41.4~50.4 Gy/23~28 fractions, and high dose rate intracavitary treatments, delivering a dose of 30~35 Gy to point A in 6~7 fractions. During intracavitary radiation, a parametrial boost was delivered for a point B dose of 60 Gy in the non-thickened side, and 65 Gy in the thickened side. Treatment related acute toxicities were assessed using Radiation Therapy Oncology Group (RTOG) acute morbidity scoring criteria. The response to treatment, and survival, were analyzed. The median follow-up period was 19 months.
RESULTS
The FIGO stage distributions of arm I (n=16) and arm II (n=14) were as follows; IIB 10, IIIA 1, IIIB 4, IVA 1 in arm I, 12, 0, 1 and 1 in arm II respectively. The compliance of both arms were 80.0% and 93.3%, respectively (p=0.37). During radiation therapy, the incidences of leukopenia, greater than RTOG grade 2, were 25.0%, 14.3%, respectively. There were no patients with gastrointestinal or genitourinary toxicity greater than RTOG grade 2. The complete response rates at 3 months, following radiation therapy, were 87.5% and 92.9% respectively. Two-year disease free survival rates were 81.3%, 85.7%, respectively, for each arms.
CONCLUSION
There was no significant difference in response to treatment, or patterns of failure, between the monthly FP and weekly cisplatin arms. Although there were no statistically significant differences, the patients of the weekly cisplatin arm had better compliance. More patients, and a longer follow up, are needed for improved evaluation of the regimen.

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5-FU Induces Apoptosis of Fas (+), HepG2 Cells Via Activation of Fas-mediated Caspase and Mitochondria Dysfunction: Channy Park, Kui hyun Yoon, Young Jin Lee, Yong Kweon Kim, Yee Cheon Choi, Jae Hoon Shin, Jeong Hwan Cho, RaeKil Park; Cancer Res Treat. 2002;34(2):128-138. Published online April 30, 2002; DOI: https://doi.org/10.4143/crt.2002.34.2.128

Abstract PDF

PURPOSE
In order to investigate the role of Fas on the chemosensitivity of cancer cells in regards to chemotherapeutic agents, the Fas/FasL signaling pathway of apoptosis was explored in human hepatoma cells.
MATERIALS AND METHODS
Fas expression of hepatoma cells including Chang, Huh7, HepG2, and Hep3B cells, was determined by RT-PCR and flow cytometry analysis. Cell viability was measured by MTT assay and apoptosis was assessed by DNA fragmentation assay. The catalytic activity of the caspase-family proteases including caspase-3, 6, 8, and 9 proteases, was tested using fluorogenic biosubstrates. The expression of apoptotic mediators including cytochrome c, PARP, and Bcl2 family proteins were measured from cytosolic and mitochondrial compartments. Mitochondrial membrane potential was measured by fluorescence staining with JC-1, rhodamine 123.
RESULTS
Fas mRNA was constitutively expressed in Chang and HepG2 as defined as Fas (+) cells, but not in Huh7 and Hep3B cells, defined as Fas (-) cells. Fas (+) cells were markedly sensitive to 5-FU whereas Fas (-) cells were resistant and able to survive. 5-FU increased Fas expression of Fas (+) HepG2 cells and simultaneously resulted in apoptotic death, characterized by the ladder-pattern fragmentation of genomic DNA. Moreover, it increased the catalytic activity of caspase-8 protease, which eventually cleaved the Bid into truncated Bid which translocated into mitochondria only in Fas (+) cells. It also increased the caspase-9 protease activity with Bax expression, cytosolic release of cytochrome c, and mytochondrial dysfunction only in Fas (+) HepG2 cells. Furthermore, 5-FU increased the enzymatic activity of caspase-3 protease with PARP digestion in HepG2 cells.
CONCLUSION
5-FU exerted cytotoxicity against hepatoma cells via activation of Fas-mediated apoptotic signaling including caspase cascades and mytochondrial dysfunction. Our data suggests that Fas may be an important modulator of the chemosensitivity of cancer cells vis- -vis anticancer chemotherapeutic agents.

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The Postoperative Adjuvant Chemotherapy with Combined 5-Fluorouracil and Mitomycin-C following curative resection for gastric Cancer: Young Suk Park, Chang In Suh, Won Ki Kang, Heung Tae Kim, Yung Jue Bang, Noe Kyeong Kim, Jae Gahb Park, Kuhn Uk Lee, Kuk Jin Choe, Soo Tae Kim; J Korean Cancer Assoc. 1989;21(2):406-413.

Abstract PDF: The postoperative adjuvant chemotherapy with 12 cycles of 5-FU and mitomycin-C has been administered in 162 patients with stage II or lll gastric adenocarcinoma after curative gastric resection. 1) After a median follow-up time of 81 months, 94/163 treated patients recurred (58%). The sites of recurrent cancer were as follows: loco-regional, 419, peritoneal, 24%, distant metastases, 26%, multiple sites, 9%. 2) The 5-year disease free survival rates were 36.8% 3) The 5-year overall survival rates were 45.0% and the median survival was 50.2 months. 4) The number of lymph nodes involvement and the T stage affected disease free and overall survival. 5) The FM regimen was well tolerated, and produced moderate bone marrow suppression, anorexia, nausea, vomiting and diarrhea.

2,932 View
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Establishment and Chemosensitivity ( 5 - FU ) Test of Colon Cancer Cell Lines with Enhanced Invasive Potential: Jae Gahb Park, Song Kim, Yung Jue Bang, Hynda K. Kleinman, Jin Pok Kim; J Korean Cancer Assoc. 1990;22(3):424-431.

Abstract PDF: The in vitro chemosensitivity of 3 human colorectal cancer cell lines and those invasive cells which were repeatedly selected with in vitra matrigel invasion assay to the anticancer agent, 5-FU, was determined using a semiautomated tetrazolium-based colorimetric assay (MTT assay). The IDvalues of control cells of SNU-C1, SNU-CZA, SNU-61 were 2.37+-4.S2ug/ml, 0.85+0.40ug/ml, 23.9+-13.3ug/ml, respectively, and those of invasive cell groups obtained by matrigel invasion assay were 0.37+-0.24ug/ml, 1.37+1.04ug/ml, 40.5+19.1ug/ml. There were no statistically significant differences between the ID,. values of control cell groups, SNU-C1(0), SNU-C2A(0), SNU-61(0) and those of invasive cell groups(p>0.05). This result was considered to be caused by the homogenization of the established cell lines during passage and maintenance cultivation.

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Anticarcinogenic Activity of Copolang : Suppression of N , N'-Dimethyl Nitrosamine - Induced Activation of Hepatic Glutathione S-Transferase: Tai Ho Chung, Jung Chul Kim, In Sun Lee, In Su Lee, Moon Kyu Kim; J Korean Cancer Assoc. 1990;22(3):431-440.

Abstract PDF: Dimethylnitrosamine (DMV)-induced renal mesenchymal preneoplastic loci and hepatic glutath- ione S-transferase P (GST-P) gene expression in weanling F344 male rats were used as early carcinogenic biomarkers to evaluate anticarcinogenicity of Copolang. Continuous daily intake of 0. 85 1.1 g Copolangiday/kg b. wt. for 3 weeks immediately following a single intraperitoneal administration of DMN (15, 30 and 60 mg/kg body weight) significantly blocked these DMN-induced biomarkers. The dose response slopes for DMN with or without Copolang treatment (1% Copolang in drinking water) were 0.27 and 0,47, respectively. Copolang treatment significantly inhibited DMN-induced small renal mesechymal cell proliferation, Likewise hepatic GST-P enzyme expression in the lowest DMN dose group (15 mg/kg) and the highest dose (60 mg/kg) was blocked nearly completely. In the highest dose group, multicellular GST-P enzyme loci were not observed in this experimental group, however, there was GST-P positive single cells were observed. On the other hand, in the middle dose group, GST-P histochemical staining was much more diffuse and not as intense. The results of this study demonstrate that Copolang treatment significantly inhibits expression of DMN-induced early carcinogenic biomarkers. A long term whole animal carcinogenic bioassay study is necessary to confirm anticarcinogenic activtiy of Copolang.

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Expression of Carcinoembryonic Antigen by Immunohistochemical Staining Method in Primary Male Breast Cancer: Hyun Cheol Chung, Dong Lip Kim, Eun Hee Koh, Joo Hang Kim, Jae Kyung Roh, Jin Sik Min, Kyung Shik Lee, Woo Ik Yang, Byung Soo Kim, Byung Soo Kim; J Korean Cancer Assoc. 1990;22(3):440-451.

Abstract PDF: Carcinoembryonic antigen (CEA) immunohistochemistry was evaluated with 12 sections of male breast cancer diagnosed at Severance Hospital during the year of 1979-1990. Ten of twelve (83.3%) primary breast masses and four of five (80%) metastatic lymph nodes were CEA positive. There was concordance of CEA positivity and CEA positivity grade between primary mass and metastatic lymph nodes. The grade of CEA positivity did not appear to be related to size, tumor depth (T) and pathological stages. It was difficult to find a relationship between nuclear grade and CEA positive grade, because there was no nuclear grade 3 patient. Tumor heterogeneity was a constant feature of CEA staining with positivity varying from region to region.

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Induction of Natural Killer and Lymphokine Activated Killer Cell Activities in Patients with Advanced Cancer Treated with Combination of Interleuki: Kyoo Hyung Lee; J Korean Cancer Assoc. 1990;22(3):451-458.

Abstract PDF: Peripheral blood lymphucytes were obtained from 14 patients with advanced cyncer receiving combination therapy with interleukin-2 (IL-2) and a-interferon (a-IFN) as a part of a phase I study and killer cell activities were assayed against k-562 and Daudi cell lines before, during, and after the therapy. There was significant natural killer (NK) activity before the treatment (74+-77 Lytic Unit) and it increased during the treatment (day 5, 262+195 L.U., p<0.01); day 15, 431+-328 L.U., p<0.01; and day 26, 743+-506 L.U., p<0.01). Lymphokine activated killer (LAK) activity before the treatment was low (13+9 L.U.) but also increased significantly during and after the treatment (day 5,71+59 L. U., p<0.01; day 15. 63+-77 L.U.; and day 26, 290+419 L.U.). In l0 patients same assay was repeated during the second course of therapy and showed similar increase in killer cell activities without evidence of cumulative increment. Out study showed that immunotherapy with combination of IL-2 and rz-IFN induces significant levels of NK and LAK cell activities in patients with advanced cancer. This biological phenomena can be utilized as a paramenter with which the IL-2 therapy can be tailored to augment clinical efficacy and tolerability.

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Effects of Lovastatin in Combination with 5-FU on Stomach Cancer Cells: Chaehwa Park, Won Ki Kang; J Korean Cancer Assoc. 1997;29(5):785-790.

Abstract PDF: No abstract available

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A Phase II Study of Oxaliplatin, 5-Fluorouracil, and Leucovorin in 5- Fluorouracil-Pretreated Metastatic Colorectal Cancer: Keun Seok Lee, Won Sup Lee, Hark Kyun Kim, Joo Young Jeong, Dae Seog Heo, Yung Jue Bang, Noe Kyeong Kim; J Korean Cancer Assoc. 2001;33(2):99-105.

Abstract PDF: PURPOSE
To evaluate antitumor response, time to progression, and toxicities of oxaliplatin, 5- fluorouracil (5-FU), and leucovorin (LV) continuous infusion in patients with metastatic colorectal cancer who progressed during or after treatment with a 5-FU-containing regimen.
MATERIALS AND METHODS
Forty-eight patients with metastatic colorectal cancer, who progressed while receiving or after discontinuing palliative chemotherapy with 5- FU-based regimen, were enrolled in this study. Treatment consisted of oxaliplatin (85 mg/m2 on day 1) as a 2-hour infusion followed by bolus 5-FU (400 mg/m2 on day 1), and 5-FU 48-hour infusion 2.4~3 g/m2 concurrently with LV 48-hour infusion 150 mg/m2, without mixing. Cycles were repeated at 2-week intervals. The dose of 5-FU was modified, depending on the hematologic toxicity profile.
RESULTS
The objective response rate was 28% for 43 assessable patients (95% confidence interval, 14% to 42%), including one complete remission (2%). Seventeen additional patients (39%) had stable disease, and fourteen (33%) progressed. The median time to progression was 5.9 months and the median overall survival was 13.2 months from the start of the chemotherapy. From the 297 cycles analyzed, hematologic toxicities per course were: leukopenia; grade I 26.6%, grade II 3.4%, and grade III 0.3%, thrombocytopenia; grade I 10.8%, grade II 3.0%, grade III 1.0%, and grade IV 0.3%. The most frequent nonhematologic adverse reactions were nausea/vomiting and peripheral neuropathy, which were rated as WHO grade II in 13 patients (49%) and 11 patients (22%), respectively.
CONCLUSION
This phase II study of oxaliplatin, 5-FU, and LV continuous infusion showed enhanced antitumor activity in patients with 5-FU-pretreated metastatic colorectal cancer. Overall toxicity was acceptable; neurotoxicity and bone marrow suppression constituted the dose-limiting side effects.

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Synergistic Antitumor Effects of 5-Fluorouracil ( 5-FU ) and Alpha-interferon 2a Gastric Cnancer Cells: Sam Yong Kim, Sang Jun Park, Jong Suk Kim, Jee Young Choi, Hwan Jung Yun, Eui Gun Chun, Deog Yeon Jo, Chin Sun Bae; J Korean Cancer Assoc. 1995;27(1):8-18.

Abstract PDF: Many in vitro studies or clinical trials reported synergistic effect of the combination of 5-FU and alpha-interferon 2a(IFNa-2a) in patients with colorectal cancer, urinary bladder cancer, and esophageal cancer. There have been few reports on the effects of the combination of 5-FU and IFN against gastric cancer ce11 lines. This study was conducted to investigate the com- bined cytotoxic effects of 5-FU or cisplatin with IFNa-2a against two gastric cancer cell lines. SNU-1 and SNU-l6 cell lines were treated with a serial concentrations of 5-FU plus IFNa-2a (5000: 1, molar ratio) and cisplatin plus IFNa-2a (400: 1, molar ratio). Cytotoxicity was determined using a tetrazolium-based colorimetric (MTT) assay. The combination effect of two drugs was evaluated by the median effect principle after Chou et aL Calculation of Assay-AUC was done after Park et aL In SNU-1 cell line, combination of 5-FU and IFNa-2a showed a synergistic effect (combination index, CI<1). Assay AUC of 5-FU was markedly reduced com- parable to clinically achievable-AUC in all combinations. In SNU-16 cell line, combination of 5- FU or cisplatin with IFNa-2a showed no synergism (CI> 1). But inhibitory concentration (IC ) value was markedly reduced. So 5-FU or cisplatin activity were markedly enhanced by IFNa- 2a, especially at low doses.

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Chemotherapy with Five-Day Continuous Infusion of 5-Fluorouracil (5-FU) Plus Cisplatin for Advanced Gastric Cancer; Significance of 5-FU Concentration Monitoring: Yeon Hee Park, Bong Seog Kim, Baek Yeol Ryoo, Tae You Kim, Young Hyuck Im, Ho Sang Shin, Yoon Koo Kang; J Korean Cancer Assoc. 2000;32(3):516-523.

Abstract PDF: PURPOSE
To investigate the therapeutic effects and toxicities of 5-day continuous infusion of 5-FU plus cisplatin FP chemotherapy in advanced gastric adendegrees Carcinoma and to elucidate the relationship between the pharmacokinetic (PK) parameters and therapeutic outcome.
MATERIALS AND METHODS
Patients with previously untreated advanced stomach cancer were treated with FP chemotherapy. Plasma concentrations of 5-FU were measured using gas chro matography method for 5 days. Correlation of PK parameters of 5-FU with clinical outcome after FP chemotherapy was studied.
RESULTS
Response rate of FP chemotherapy was 46% (95% C.I.: 30~62%). There was a wide range of difference in the concentration and area under the curve (AUC) of 5-FU from patient to patient. We could find significant differences in AUC of 5-FU between the responders and the non-responders (p<0.05).
CONCLUSION
We could confirm that FP chemotherapy was effective and tolerable for the treatment of advanced stomach cancer. The monitoring of plasma 5-FU concentration after chemotherapy and the adjustment of subsequent 5-FU dose seems to be necessary to improve the treatment outcome of FP chemotherapy.

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