Annals of Coloproctology

Original Articles

Invasiveness of and Drug Sensitivity to Various Anti-cancer Regimens in Five Colorectal Cancer Cell Lines.: Lee, Yoo Mi , Yoon, Yong Sik , Roh, Seon Ae , Cho, Dong Hyung , Kim, Jin Cheon; J Korean Soc Coloproctol. 2010;26(2):98-104.; DOI: https://doi.org/10.3393/jksc.2010.26.2.98

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PURPOSE
Colorectal cancer (CRC) is one of the leading causes of cancer death in South Korea. Angiogenesis has been associated with invasion and metastasis of tumors and with the secretion of various growth factors. Bevacizumab is a humanized monoclonal antibody that recognizes and blocks vascular endothelial growth factor (VEGF) and that targets integrin alphaVbeta3 and matrix metalloproteinases (MMPs) as angiogensis inhibitors. The aims of this study were identification of the mechanism of target molecules related to angiogenesis and demonstration of identifiable invasion by using chemotherapeutic regimens in vitro.
METHODS
The five colorectal cancer cell lines were treated with bevacizumab using standard or combined regimens. The expression of integrin alphaVbeta3 was detected and the investigation of apoptosis was done by using flow cytometry. The activations of MMP-2 and MMP-9 were measured by using gelatin zymography.
RESULTS
The apoptotic cell death was significantly increased for the combined regimens, especially for FOLFOX (5-FU, leucovorin, and oxaliplatin) with bevacizumab. Bevacizumab inhibited the expression of integrin alphaVbeta3 in the HT29 (59%), LoVo (67%), and SW480 (17%) cell lines, but did not in the AMC5 and the RKO cell lines. The activations of MMP-2 and MMP-9 were significantly reduced by treatment with bevacizumab in the HT29 and the LoVo cell lines. In the HT29 and the LoVo cell lines, thus, bevacizumab inhibited invasion and metastasis activity through down-regulation of integrin alphaVbeta3 and MMPs.
CONCLUSION
Our results provide biological evidence of potent angiogenic activity and indicate that angiogenesis is a complex process that involves multiple factors, including VEGF, integrin alphaVbeta3, and MMPs.

Citations

Citations to this article as recorded by

RGD peptide in cancer targeting: Benefits, challenges, solutions, and possible integrin–RGD interactions
Hossein Javid, Mahsa Akbari Oryani, Nastaran Rezagholinejad, Ali Esparham, Mahboubeh Tajaldini, Mehdi Karimi‐Shahri
Cancer Medicine.2024;[Epub] CrossRef

Safety of Early Chemotherapy after a Laparoscopic Colorectal Cancer Resection: A Case-Control Study.: Shin, Seung Ho , Lee, Sun Il , Choi, Dong Jin , Woo, Si Uk , Kim, Jin , Min, Byung Wook , Moon, Hong Young , Kim, Seon Hahn; J Korean Soc Coloproctol. 2009;25(6):429-436.; DOI: https://doi.org/10.3393/jksc.2009.25.6.429

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Abstract PDF: PURPOSE
Since micrometastasis is generally inhibited by primary cancer, surgical ablation of the tumor may stimulate the growth of residual cancer cells, if they exist. This supports the importance of early administration of postoperative chemotherapy. METHODS: We reviewed the cases of patients who underwent a laparoscopic resection and then received chemotherapy (5 fluorouracil+leucovorin or FOLFOX4) between September 2006 and May 2008. The chemotherapy was scheduled on the 7th or the 8th postoperative day, but was postponed when a final pathologic report was delayed or patients were discharged early. The safety of chemotherapy was evaluated in two ways. Early safety, such as the presence of surgical complications and medical toxicity, was prospectively assessed just before the beginning of the second cycle of chemotherapy. Late safety, such as medical toxicity, was retrospectively estimated from the 2nd to the last cycle. These safeties were compared between the two groups: the early chemotherapy group (n=50) for which chemotherapy started on the 7th or 8th postoperative day as scheduled and the delayed chemotherapy group (n=31) for which chemotherapy started after the 14th postoperative day.
RESULTS
Patient demographics were not different between the two groups. With regards to early safety, no differences in surgical complications existed between the two groups. In medical toxicities, there were no differences, except for a higher rate of nausea in the early chemotherapy group (20 percent vs. 10 percent, P=0.01). With regards to late safety, the two groups were not different in the development of medical toxicities. CONCLUSION: Because nausea is an easily controllable toxicity, we conclude that chemotherapy is safely started on the 7th or the 8th day after a laparoscopic colorectal cancer resection.

Review

Imrpoving Outcomes with Chemotherapy in Colorectal Cancer: Current Options, Current Evidence.: Kim, Ik Yong; J Korean Soc Coloproctol. 2006;22(2):137-149.

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Abstract PDF: The last several years have major advances in chemotherapy treatment for adjuvant and metastatic colorectal cancer. We've come from an overall survival of 6 months in patients treated with best supportive care in the mid 1980s and even in the early 1990s. The use of 5-FU/leucovorin alone generates an overall survival of about 6 months. The addition of irinotecan/oxaliplatin allows patients to live a median of about 15 to 17 months. If we make use of all 3 active drugs, FOLFOX and FOLFIRI in a sequential manner, we'll be able to generate an overall survival of about 20 months. Recently, the addition of molecular therapy, in particular bevacizumab and cetuximab to these cytotoxic drugs has allowed us to break the brick wall that was placed at about 2 years median overall survival in large phase 3 trials in patients with metastatic colorectal cancer. The recent presentations provided further evidence that the standard of care in the treatment of advanced CRC consists of a combination of highly active cytotoxic chemotherapy plus the addition of a biologic agents, For clinical research, investigation of the best therapy for CRC has clearly shifted away from investigating conventional chemotherapy toward the question of how to make best use of all available active agents, particularly the novel biologics. Randomized trials have also shown that preoperative chemoradiation yields higher rates of pathologic complete response and local control, compared with radiotherapy alone. In this article, I review recent trials on preoperative and adjuvant therapy of localized rectal cancer. The roles of newer agents, such as capecitabine, oxaliplatin, and bevacizumab, are also discussed, and other key issues in the treatment of localized rectal cancer are reviewed. The planned phase 3 first-line trial will continue to elucidate the role of the currently available biologics in the treatment of CRC. In this article, the important advances in optimal chemotherapy of colorectal cancer will be summarized and approaches to multidisciplinary treatment decision-making in both adjuvant and metastatic settings will be reviewd.

Original Article

Differences of Response Rates according to Metastatic Sites after Oxaliplatin, 5- Fluorouracil, and Leucovorin Combination Chemotherapy (FOLFOX 3) in Advanced Colorectal Cancer.: Lee, Seung Hyun , Ahn, Byung Kwon , Baek, Sung Uhn; J Korean Soc Coloproctol. 2005;21(1):42-47.

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Abstract PDF: PURPOSE
Oxaliplatin is a recently developed active agent in colorectal cancer. Clinical observations have demonstrated synergistic effects of oxaliplatin with 5-fluorouracil (5- FU) and leucovorin (LV), even in 5-FU-resistant colorectal cancer. The purpose of this study was to determine response rates according to clinical factors after oxaliplatin, 5-FU and LV combination chemotherapy (FOLFOX 3) in metastatic colorectal cancer.
METHODS
We reviewed 44 patients who had received FOLFOX 3 from Jan. 2000 to Dec. 2002. The combination chemotherapy consisted of oxaliplatin (85 mg/m2 on day 1) as a 2~6 hour infusion followed by continuous infusion of 5-FU (1500 mg/m2 on day 1, 2), concurrently with LV (45 mg on day 1, 2) as a 2 hour infusion. Cycles were repeated by 2-week intervals. We compared the response rates according to clinical factors such as primary sites, cycle, tumor differentiation, metastatic sites, serum CEA, and previous chemotherapy.
RESULTS
Of the 44 patients who had received the combination chemotherapy with oxaliplatin, 5-FU, and LV, 19 cases were male, 25 cases were female. The median age was 50.7 years. The primary tumor sites were colon in 21 cases (47.7%), and rectum in 23 cases (52.3%). The metastatic sites were liver in 27 cases (61.4%), lung in 9 (20.5%), pelvis in 3, lymph node in 5, and peritoneum in 1. Thirty- five patients had received the combination chemotherapy as first line. Complete response was observed in 3 cases (6.8%). Partial response was in 7 cases (15.9%), stable disease status in 15 cases (34.1%), progressive disease status in 19 cases (43.2%), respectively. There were a no significant differences in response rates according to primary sites, tumor differentiation, serum CEA, and previous chemotherapy. However, with the metastatic sites, there were significant differences in response rates. Response rates were higher in lung (5/9), lymph node (3/4) metastases than any other metastatic sites (P <0.01).
CONCLUSIONS
The objective response rate of FOLFOX 3 was 22.7% in metastatic colorectal cancers. The only significant clinical factor was metastatic sites. The lung and lymph node metastases showed better response than metastatses to liver, pelvis, and peritoneum. To evaluate the differences of response rates according to metastatic sites, we need further study.

Review

New Trend in Chemotherapy for Colorectal Cancer.: Kim, Young Jin , Kim, Hung Dai; J Korean Soc Coloproctol. 2004;20(2):118-123.

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Abstract PDF: 5-Fluorouracil (5-FU) has been the main chemotherapeutic agent for the treatment of colorectal cancer for four decades with modest efficacy. Modulation of 5-FU by leucovorin or continuous infusion improves the response rate, but overall survival duration remains approximately 12 months. Many oral fluoropyrimidines have been studied, including capecitabine, UFT, S-1, and Eniluracil. Capecitabine has demonstrated equivalent efficacy with 5-FU and has been approved as first line treatment. CPT-11 demonstrated non-crossover resistance with 5-FU and was proven to be effective treatment for patients who received prior 5-FU. CPT-11 in combination with 5-FU has demonstrated improved response rate and overall survival duration over 5-FU or CPT-11. Oxaliplatin plus 5-FU has offered another effective treatment option for colorectal cancer. Both 5-FU plus leucovorin in combination with CPT-11 or oxaliplatin are widely used first-line chemotherapies for advanced colorectal cancer. The combinations of capecitabine with CPT-11 or oxaliplatin are being developed. Several molecular targeting agents such as EGFR inhibitors and antiangiogenic agents have developed. Cetuximab induces a broad range of cellular responses in tumors expressing EGFR, enhancing sensitivity to radiotherapy and chemotherapeutic agents. A key angiogenic pathway in the stimulation of tumour growth is the vascular endothelial growth factor (VEGF) pathway, inhibited by the monoclonal antibody bevacizumab. Phase II first line and phase III second line studies of oxaliplatin in combination with bevacizumab are now in progress. Optimal combinations and sequences of treatment are being studied, since several effective regimens have become available.

Original Article

Clinical Trial of Oxaliplatin, 5-Fluorocuracil, and Leucovorin in Advanced Colorectal Cancer: 48 Cases.: Lee, Seung Hyun , Ahn, Byung Kwon , Baek, Sung Uhn; J Korean Soc Coloproctol. 2002;18(6):402-407.

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Abstract PDF: PURPOSE
Although 5-fluorouracil (5-FU) has been used as the basis of chemotherapy regimen for colorectal cancer for more than 40 years, 5-FU as single agent treatment has rarely achieved objective response rates higher than 15% in advanced colorectal cancers. The modulation of 5-FU with biologic modifiers has resulted in higher response rates, but survival advantages was not meaningful. Oxaliplatin is one of the newly developed drugs with proven activity against colorectal cancer. To evaluate the therapeutic efficacy and safety profile of oxaliplatin, we reviewed patients who received oxaliplatin chemotherapy.
METHODS
We reviewed 48 patients who received combination chemotherapy with oxaliplatin, 5-FU, and leucovorin (LV) from Jan. 2000 to Dec. 2001. The combination chemotherapy consisted of oxaliplatin (85 mg/m2 on day 1) as a 2~6 hour infusion followed by continuous infusion of 5-FU (1,500 mg/m2 on day 1, 2), concurrently with LV (45 mg on day 1, 2) as a 2 hour infusion. The combination chemotherapy interval was 2 weeks.
RESULTS
Of the 48 patients who received the combination chemotherapy with oxaliplatin, 5-FU, and LV, 25 cases were male, 23 cases were female. The median age was 51.4 years. The primary tumor sites were colon in 22 cases, and rectum in 26. According to TNM stage at diagnosis, 1 case was stage I, 5 cases were stage II, 21 cases were stage III, and 21 cases were stage IV. The metastatic sites were liver in 29 cases, lung in 10, pelvis in 7, peritoneum in 5, bone in 1, lymph node in 1, and spleen in 2. Previous chemotherapy were Mayo regimen in 43 patients, irrinotecan in 1 patient. Four patients had not received previous chemotherapy. Previously of the 48 patients, we could assess the chemotherapy response for 25 cases. Complete response was not observed. Partial response was 3 cases (12%), stable disease in 12 cases (48%), progressive disease in 10 cases (40%). From 227 cycles analyzed, the main toxicity was gastrointestinal one. Peripheral neuropathy was identifed in 5 cases.
CONCLUSIONS
We reviewed 48 patients with advanced colorectal cancer who received combination chemotherapy with oxaliplatin, 5-FU and LV. Of the 25 evaluable patients, the objective response rate was 12%. In our study, the combination chemotherapy with oxaliplatin, 5-FU, LV has not resulted in improved response rate, but overall toxicity was acceptable.

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