[show abstract][hide abstract] ABSTRACT: The leucovorin (FOL) and fluorouracil (5-FU) plus oxaliplatin (l-OHP; FOLFOX) or FOL and 5-FU plus irinotecan (SN-38; FOLFIRI) regimens with or without molecularly-targeted drugs are widely used as first-line chemotherapy in the treatment of advanced colorectal cancer (CRC). Whether FOLFOX or FOLFIRI is administered first is not significant, however, it is essential that full administration of the targeted dosages of all 3 drugs, 5-FU, l-OHP and SN-38, is achieved. However, this is not always possible and second-line chemotherapy must be abandoned in certain cases. Where possible, the most effective regimen should be selected as the first line of treatment. The aim of this study was to determine whether first-line chemotherapy may be individualized using the collagen gel droplet-embedded drug sensitivity test (CD-DST). Specimens of primary tumors were obtained from 43 CRC patients who had received no preoperative chemotherapy. Informed consent to measure drug sensitivity was obtained from all patients. The CD-DST allows evaluation of drug sensitivity using isolated, 3-dimensionally cultured tumor cells in a small collagen gel droplet. The CD-DST was performed and the growth inhibition rate (IR) was obtained under incubation conditions (5-FU with l-OHP at 6.0 and 3.0 μg/ml, or 5-FU with SN-38 at 6.0 and 0.2 μg/ml, respectively, for 24 h). The cumulative distributions of the growth IRs under each condition were evaluated based on the evidence that the clinical response rates to FOLFOX and FOLFIRI were almost the same. Individualization of first-line treatment was possible in all patients, with FOLFOX and FOLFIRI showing higher efficacy in 26 and 15 patients, respectively, and equal efficacy in 2 cases. This method has the potential to facilitate the establishment of individualized first-line chemotherapy for CRC and improve the prognosis in such patients.
[show abstract][hide abstract] ABSTRACT: The effectiveness of cetuximab (Cmab) against KRAS p.G13D mutant-type tumors has been reported. In this study, we report a case of metastatic ascending colon cancer harboring a KRAS p.G13D mutation in a 65-year-old female. Considering the absence of symptoms and the post-operative risk of respiratory system complications due to multiple lung metastases, particularly at the entrance to the left main bronchus, anticancer drug therapy was selected as first-line therapy. With informed consent, FOLFOX4 [folinic acid (FOL), fluorouracil (F) plus oxaliplatin (OX)] + Cmab therapy was administered as preoperative chemotherapy. A good preoperative response was obtained to the chemotherapy, with a metastatic lesion disappearing from the entrance to the left main bronchus. Subsequent resection was performed successfully with no post-operative complications. Although a histopathological examination of the resected tissue specimen revealed residual cancer cells, it also showed the marked efficacy of the chemotherapy regimen used. In this study, we describe a case of metastatic ascending colon cancer harboring a KRAS p.G13D mutation in which the patient responded well to first-line therapy with FOLFOX4 + Cmab.
[show abstract][hide abstract] ABSTRACT: We previously reported the 5-fluorouracil (5-FU) sensitivity of cancer cells obtained from colorectal cancer (CRC) patients using the collagen gel droplet-embedded culture-drug sensitivity test (CD-DST). Multiple drug concentrations and contact durations, and the area under the concentration curve (AUC) and growth inhibition rate (IR) were combined, resulting in the AUC-IR curve, which was approximated to the logarithmic curve. Moreover, the individualized AUC(IR50), the AUC value which gives 50% growth inhibition, was calculated using the AUC-IR curve. This study aimed to identify responders/non-responders to 5-FU based on the individual AUC(IR50) obtained with CD-DST in order to establish individualized chemotherapy for CRC patients. The individual AUC(IR50) was calculated from each AUC-inhibition rate regression curve in all patients using the CD-DST. The cumulative distribution of the individual AUC(IR50) in CRC patients was evaluated. The cumulative distribution of the individual AUC(IR50) was regressed over the sigmoid curve (logarithmic scale). The approximate expression was almost exactly y=ab^exp(-cx) (a=0.9739, b=1.7096E-21, c=0.8990, the sum of square residuals, 0.0279). In the 80 cases examined, no notable change was observed in the regression curve when the number of patients increased. A standard curve was obtained describing responders to 5-FU among all CRC patients. From this standard curve, we ascertained that non-responders accounted for approximately 5% of all patients. Moreover, we were able to classify responders into good or intermediate responders to 5-FU. The standard curve describing response to 5-FU in CRC patients offers a useful tool in the establishment of individualized chemotherapy.
[show abstract][hide abstract] ABSTRACT: The purpose of this study was to determine the effect of the addition of oxaliplatin (l-OHP) or irinotecan (SN-38) to 5-fluorouracil (5-FU) using the collagen gel droplet embedded culture-drug sensitivity test (CD-DST) to establish whether leucovorin plus 5-FU should be administered in combination with l-OHP (FOLFOX) or SN-38 (FOLFIRI) in individualized first-line chemotherapy for the treatment of advanced colorectal cancer (CRC). Specimens of primary tumors were obtained from 24 CRC patients who had received no preoperative chemotherapy. CD-DST was performed, and the inhibition rate (IR) was obtained under multiple incubation conditions. The effects of addition of l-OHP or SN-38 were evaluated for the same area under the concentration curve (AUC) of 5-FU based on linear regression analysis. Approximate expression and correlation coefficients (5-FU vs. 5-FU + l-OHP, 5-FU vs. 5-FU + SN-38; AUC of 5-FU=72 and 5-FU vs. 5-FU + l-OHP, 5-FU vs. 5-FU + SN-38; AUC of 5-FU=144) were y=0.94x+8.53 (R(2)=0.95, p<0.0004), y=0.77x+26.18 (R(2)=0.76, p<0.0004) and y= 0.91x+10.90 (R(2)=0.94, p<0.0004), y=0.52x+44.61 (R(2)=0.60, p<0.0004), respectively. Approximate expression of 5-FU vs. 5-FU + l-OHP almost fit the regression line (y=x+b(1)). This suggests that addition of l-OHP yields a constant additive effect, independent of the IR of 5-FU. However, approximate expression of 5-FU vs. 5-FU + SN-38 fit the regression line (y=ax+b(2), a<1, b(2)≥b(1)). This suggests that addition of SN-38 yields a greater additive effect due to the lower IR of 5-FU. These results indicate that FOLFIRI should be selected as the first-line chemotherapy for the treatment of poor responders to 5-FU.
Experimental and therapeutic medicine 01/2010; 1(2):325-329. · 0.34 Impact Factor
[show abstract][hide abstract] ABSTRACT: FOLFOX4 and FOLFIRI are effective regimens for the treatment of advanced colorectal cancer, and their use together with molecular targeting drugs has recently become more common. In the present study, we evaluated the changes in the serum iron levels of patients undergoing FOLFOX4 or FOLFIRI therapy alone or in combination with bevacizumab (BV). The serum iron level was increased 48 h after therapy and was restored to baseline 2 weeks afterwards in colorectal cancer patients who received FOLFOX4 or FOLFIRI alone or in combination with BV. This transient increase in serum iron was observed repeatedly during chemotherapy. The serum iron level was 71.66±28.96 μg/dl (mean ± standard deviation) before treatment and significantly increased to 186.82±83.17 μg/dl (p<0.001) 48 h after therapy. A transient increase in serum iron levels was also observed when FOLFIRI was administered to a patient after tumor resection. In contrast, no decrease in blood hemoglobin, no increase in liver enzymes and no increase in urinary iron excretion were observed. Based on these results, it can be concluded that an increase in serum iron may be induced by a transient change in iron distribution within the body after FOLFOX4/FOLFIRI therapy with or without BV.
Experimental and therapeutic medicine 01/2010; 1(3):507-511. · 0.34 Impact Factor
[show abstract][hide abstract] ABSTRACT: The efficiency of new anti-cancer drugs such as the S-1 system was demonstrated in a controlled study comparing treatment and non-treatment groups. We encountered a patient with gastric cancer demonstrating peritoneal dissemination, who was successfully treated by combination therapy using S-1 and docetaxel. A 62-year-old woman was admitted to the hospital due to appetite loss and nausea. Upper GI endoscopy demonstrated a type 3 gastric cancer extending from the upper to lower body of the stomach. In the pelvic cavity, an abdominal CT scan demonstrated massive ascites. An abnormally high CA72-4 (143.8 U/mL) level was detected in serum. Treatment with S-1 and docetaxel was started with the following regimen: daily oral administration of 80 mg/body S-1 for 14 days, followed by a 7-day rest and infusion of 40 mg/m2 docetaxel on day 1. After 4 courses, the sites of dissemination had disappeared, and the serum CA72-4 value returned to normal. The patient clinically achieved good QOL by this method, which was very effective for non-resected gastric cancer with peritoneal dissemination.
Gan to kagaku ryoho. Cancer & chemotherapy 09/2009; 36(9):1545-8.
[show abstract][hide abstract] ABSTRACT: We have previously reported the 5-fluorouracil (5-FU) sensitivity of cancer cells from colorectal cancer (CRC) patients using the collagen gel droplet embedded culture-drug sensitivity test (CD-DST) under multiple drug concentrations and contact durations. Moreover, the area under the concentration curve (AUC) and growth inhibition rate (IR) were combined, resulting in the AUC-IR curve, which was approximated to the logarithmic curve. In the present study, we used the AUC-IR curve to calculate the individualized AUCIR50, the AUC value that imparts 50% growth inhibition. Individual AUCIR50 was calculated in CRC patients, and its distribution was evaluated. The cumulative distribution of individual AUCIR50 was regressed over two lines (logarithmic scale). Among the 45 resectable CRC patients, those who achieved more than the individual AUCIR50 during post-operative 5-FU-based chemotherapy demonstrated a trend towards better disease-free survival compared to those who did not achieve AUCIR50. Of the Dukes' D patients (n=10), those who achieved more than twice the individual AUCIR50 during post-operative 5-FU-based chemotherapy demonstrated significantly better survival rates (p=0.05) than those who did not. In this study, the distribution of the individual AUCIR50 suggested that approximately 6% of patients demonstrated very low 5-FU sensitivity. Therefore, the individual AUCIR50 was useful in classifying good, intermediate and poor 5-FU response. Achievement of the individual AUCIR50 may be a prerequisite for individualized 5-FU-based adjuvant chemotherapy. As well, the early achievement of twice the individual AUCIR50 may indicate an improved prognosis in Dukes' D patients. The individual AUCIR50 using CD-DST is useful in determining the individualized chemotherapy of CRC patients, thus CD-DST has the potential to facilitate the establishment of individualized chemotherapy for CRC.
Molecular Medicine Reports 01/2009; 2(3):405-9. · 1.17 Impact Factor
[show abstract][hide abstract] ABSTRACT: We have evaluated the 5-fluorouracil sensitivity of cancer cells from colorectal cancer patients using the collagen gel droplet embedded drug sensitivity test under multiple drug concentrations and contact durations. After converting drug concentration and contact time to the area under the curve (AUC) and plotting against the growth inhibition rate, the correlation between AUC and the growth inhibition rates was approximated to the logarithmic regression curve. In this study, to further validate the reliability of the regression curve, the growth inhibition rate was calculated from the regression curve and the actual growth inhibition rate was compared at AUC of 48 mug h/ml. No significant difference was observed in the growth inhibition rates between the two groups by paired t-test (P=0.590). A strong positive correlation was found between the two groups by regression analysis (y=0.7555x+10.514, R=0.8236). This result strongly suggests that in-vitro antitumor effect of 5-fluorouracil depends on the AUC in colorectal cancer and the AUC-inhibition rate curve is reliable. We can obtain the inhibition rate from AUC and vice versa using the AUC-inhibition rate curve. We can also calculate the individualized AUCIR50, AUC value that gives 50% growth inhibition, using the AUC-inhibition rate curve. This could be useful to establish individualized chemotherapy using the collagen gel droplet embedded drug sensitivity test.
[show abstract][hide abstract] ABSTRACT: Phosphoribosylation of 5-fluorouracil (5-FU) is an essential step which leads to tumor growth inhibition and orotate phosphoribosyl transferase (OPRT) is the main enzyme that involves in this conversion of 5-FU to 5-fluorouridine monophosphate. This retrospective study was aimed to evaluate the correlation between tumor OPRT activity and the clinical outcome in colorectal cancer (CRC) patients treated by oral 5-FU-based adjuvant chemotherapy.
Surgical specimen was obtained from resectable 124 CRC patients who were subsequently treated by oral 5-FU-based adjuvant chemotherapy. OPRT activity in the extract of tumor tissue was enzymatically determined. The cut-off value of intratumor OPRT activity against disease free survival was determined by maximal chi2 method. The disease free survival and overall survival in each group were calculated using the Kaplan-Meier method.
Patients were divided into two groups by determined cut-off value of intratumor OPRT (0.147 nmol/min/mg protein) (high group: n = 102, low group: n = 22). Five-year DFS (P = 0.035) and OS (P = 0.020) were significantly better for high OPRT group.
This study demonstrated that an assay of tumor OPRT contributes to the determination of 5-FU-based adjuvant chemotherapy outcome and application in clinical practice should be included in tumor analysis prior to 5-FU-based adjuvant chemotherapy.
Journal of Surgical Oncology 08/2006; 94(1):45-50. · 2.64 Impact Factor
[show abstract][hide abstract] ABSTRACT: Orotate phosphoribosyl transferase (OPRT) is the main enzyme that involves in phosphoribosylation of 5-fluorouracil (5-FU), an essential step that leads to tumor growth inhibition. In our study, the prognostic relevance of OPRT, thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) in resectable colorectal cancer (CRC) patients treated by oral 5-FU were compared to further clarify the prognostic value of OPRT. Tumor tissue was collected from 90 CRC patients and the patients were followed for 5.2 years (Median). TS, DPD and OPRT activities in the extract of tumor tissue were determined enzymatically. The cut-off value of OPRT (0.147 nmol/(min mg), TS (0.044 pmol/mg) and DPD (72.10 pmol/(min mg) were determined by maximal chi(2) method. Among these 5-FU metabolic enzymes, only high OPRT group demonstrated significantly better disease-free survival (DFS) (p = 0.0152) and better overall survival (p = 0.0078). In Cox regression analysis, node status (p < 0.0005) and OPRT (p = 0.044) were significant factors for DFS. OPRT activity in tumor tissue was a predictor of prognosis in resectable CRC patients treated by oral 5-FU-based adjuvant chemotherapy, and was useful to pick-up high risk patients independent from known prognosis factors.
International Journal of Cancer 07/2006; 118(12):3084-8. · 6.20 Impact Factor
[show abstract][hide abstract] ABSTRACT: The effect of gastrectomy on pharmacokinetics after S-1 administration was investigated in a total of 12 cases - nine in which partial gastrectomy was performed and three in which total gastrectomy was performed. A single oral dose of S-1, 50 mg as tegafur, was administered, serial peripheral blood samples were collected, and the concentrations of 5-fluorouracil (5-FU) and gimeracil (CDHP) were measured. The pre-operative S-1 dose was administered about 7 days before surgery and the post-operative dose was administered around post-operative hospital day 14. In the partial gastrectomy cases the maximum post-operative blood concentration (Cmax) of 5-FU and CDHP tended to be lower than before surgery, and the difference in 5-FU concentrations was significant. The area under the blood concentration-time curve (AUC0-8 h) for CDHP was significantly smaller post- than pre-operatively, but no significant difference was observed with regard to 5-FU. In the total gastrectomy cases the post-operative tmax of both 5-FU and CDHP was shorter than the pre-operative tmax, and no significant differences were observed between the pre- and post-operative AUC0-8 h values. Thus, the results of the present study showed that around post-operative hospital day 14, when total oral feeding had become possible after surgery for gastric cancer, the AUC0-8 h values of 5-FU and CDHP after S-1 administration were almost the same as before surgery and that gastrectomy had hardly any effect on the pharmacokinetics of S-1.
[show abstract][hide abstract] ABSTRACT: Orotate phosphoribosyl transferase (OPRT) is an enzyme playing an important role in exertion of the effect of 5-fluorouracil (5-FU). A type of gene polymorphism, single nucleotide polymorphism (SNP), is considered to be a factor affecting individual differences in exertion of drug effects, and its analysis has recently made progress. We investigated the correlation between SNP of OPRT and 5-FU sensitivity in colon and rectal cancers. The subjects were 31 patients with colorectal cancer who underwent surgical excision between December 2003 and July 2004 at our department. Of SNP of OPRT, 638G/C, 1050T/A, and 1336A/G located in the coding region were analyzed by invader assay. The growth inhibition rate (% IR) of colorectal cancer by 5-FU was obtained by the CDDST method, and 5-FU sensitivity was compared among strains (wild-, homo-, and hetero-types) of each polymorphism. There was no relationship between the strains and 5-FU sensitivity in any of the SNPs. The investigated SNPs of OPRT may have no major influence on 5-FU sensitivity. However, there are many unknown factors in the relationship between SNP of OPRT and 5-FU sensitivity, and SNP analysis of other regions is necessary.
[show abstract][hide abstract] ABSTRACT: Orotate phosphoribosyl transferase (OPRT) is an essential nucleotide metabolic enzyme for cell proliferation and also a key enzyme for conversion of 5-FU to its active form in tumor tissue. The association between tumor OPRT activity and pathophysiological status, including lymph node metastasis [pN+], and the impact of OPRT for predicting pN+ were investigated in gastric cancer. The lymph node status of 73 resectable gastric cancer patients was analyzed preoperatively by computed tomography (CT), ultrasonography and magnetic resonance, and the OPRT activity of collected tumor tissue was measured. Then these data were compared with pathological observation of a surgical lymph node specimen. OPRT activity in the tumor tissue decreased as the depth of invasion increased. An OPRT test demonstrated superior sensitivity and comparable accuracy and sensitivity for predicting pN+, against current imaging diagnoses. Furthermore, the analysis of node negative patients by CT revealed that 80% of false negative patients were retrieved by this OPRT test. Thus, OPRT activity in tumor tissue was a powerful predictor of pN+ in resectable gastric cancer, and the preoperative OPRT test, when it becomes possible, would provide a basis for accurate evaluation of disease status, which is indispensable for the planning of personalized therapy.
[show abstract][hide abstract] ABSTRACT: The drug sensitivity of tumor cells is one of key issues to explore individualized therapy for cancer patients. One of such methods is in vitro anticancer drug sensitivity test which is generally based on one drug concentration and contact time. In this study, 5-fluorouracil (5-FU) sensitivity of cancer cells from colorectal cancer patients was evaluated by collagen gel droplet embedded drug sensitivity test (CD-DST) under multiple drug concentrations and contact durations. Cancer cells from 19 patients were measured for 9 drug concentration/contact time conditions (cohort 1) and from 34 patients were measured for 2 drug concentration/contact time conditions (cohort 2) using CD-DST. There was not significant difference in growth inhibition rate for 1.0 microg/ml for 24 h and 0.2 microg/ml for 120 h, which gives the same area under the curve (AUC) (p=0.832) in all 53 patients (cohort 1 and 2). In cohort 1, 9 conditions were successfully measured in 18 of 19 cohort 1 patients (94.7%). The drug concentrations and growth inhibition rate approximated to logarithmic curve for all 3 contact times and 50% inhibitory concentration (IC50) values at 3 contact times could be calculated in these 18 patients. Growth inhibition rate and AUC also approximated to logarithmic curve. These values varied several orders of magnitude among patients. In vitro antitumor effect of 5-FU depended on AUC in colorectal tumor and it might support the use of continuous infusion or oral therapy which generates significant AUC with manageable toxicity. Some patients demonstrating low 5-FU sensitivity could not be indicated for 5-FU based therapy, and non-5-FU therapy should be explored for them.
[show abstract][hide abstract] ABSTRACT: We invented the Perineum Pusher to prevent excessive extension of the rectum by elevating the bottom of the pelvis. In the treatment of cancers of the middle and lower thirds of the rectum, a clear operative view can be maintained for a long time by using the Perineum Pusher. Consequently, a sphincter-saving rectal resection with coloanal anastomosis can be performed easily and safely. In addition, intraoperative rectal irrigation can be performed using the Perineum Pusher. No complications resulting from the Perineum Pusher have been experienced in 27 rectal cancer patients. As the Perineum Pusher can be used very simply and effectively in sphincter-saving rectal resections with coloanal anastomosis, this new surgical instrument is therefore highly recommended for use when performing various rectal procedures.
Surgery Today 02/2004; 34(7):639-41. · 0.96 Impact Factor
[show abstract][hide abstract] ABSTRACT: To identify factors that influence the clinical response to 5-fluorouracil (5-FU), we studied the correlation between in vitro sensitivity to 5-FU and the expression of seven biological markers. The markers, thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), pyrimidine nucleoside phosphorylase, p53 (wild/mutant), p21, cyclo-oxygenase-2, and inducible nitric oxide synthase were measured in tumour tissues from 32 colorectal cancer patients. The activities of TS and DPD were significantly lower in the tumours sensitive to 5-FU compared with those that were not sensitive to 5-FU. In tumours with TS < 3.7 pmol/min per mg protein and DPD < 98 pmol/min per mg protein, the percentage of cases sensitive to 5-FU (67%) and the mean percentage inhibition of tumour cells by 5-FU (42.8%) were significantly higher than in the other tumours (0% and 13.1%, respectively). The other biological markers did not correlate with in vitro sensitivity to 5-FU. Tumour sensitivity to 5-FU can be more precisely predicted by taking the activities of both TS and DPD into consideration than by using either alone.
The Journal of international medical research 06/2003; 31(3):181-7. · 0.96 Impact Factor
[show abstract][hide abstract] ABSTRACT: A laparoscopic cholecystectomy (LC) was successfully performed on a 61-year-old man who had undergone coronary artery bypass grafting (CABG) using the right gastroepiploic artery (RGEA). He complained of right hypochondralgia 20 days after CABG. Gallstones were diagnosed and a cholecystectomy was performed 9 months after CABG. Under general anesthesia, the operation was performed using a pneumoperitonium. When a laparoscope was inserted, the RGEA pedicle could be clearly recognized. The pedicle obstructed the operating field and made the working space narrower than usual. No ST changes on the electrocardiogram were seen during LC, especially during the initiation of pneumoperitonium, the insertion of the ports, or when retracting the gallbladder. The postoperative course was uneventful. To avoid complications, care should be taken not to stretch the RGEA pedicle during LC, and careful monitoring of the electrocardiogram is also necessary. It is difficult to view the operating field and the RGEA pedicle together. It is therefore better to insert another laparoscope for concomitant monitoring of the RGEA pedicle.
Surgery Today 02/2002; 32(9):840-3. · 0.96 Impact Factor