Circulating and tumor miR-21 could predict irinotecan sensitivity in gastric cancer / 中国癌症杂志

Background and purpose:Mir-21 has been demonstrated high expressed in many kinds of tumor tissues and cell lines. High expressed miR-21 leads to chemoresistance. Circulating miRNA is a novel biomarker for chemosensitivity prediction. The aim of our study was to investigate the role of plasma and tumor miR-21 levels as predictive biomarkers for irinotecan in gastric cancer. Methods: The histoculture drug response assay (HDRA) was used to determine irinotecan and cisplatin sensitivity on 35 freshly removed gastric tumor specimens. miR-21 expressions in tumor and plasma were determined by quantitative reverse transcription polymerase chain reaction. Results:Plasma miR-21 was closely correlated with corresponding miR-21 mRNA level in tumor tissues (rho=0.736, P<0.001) and was not correlated with sex, age, pathology type, differentiation, lymph node metastasis, TNM stage or tumor location. Patients with stage Ⅱ-Ⅲhad higher miR-21 levels. The tumor miR-21 expressions in cisplatin-sensitive group and resistant group were 1.32 (95%CI:0.73-1.90) and 4.06 (95%CI:1.71-6.41)(P=0.004), respectively. The plasma miR-21 expressions in cisplatin-sensitive group and resistant group were 5.25 (95%CI:0.14-10.64) and 5.82 (95%CI: 2.27-9.37)(P=0.19). The tumor miR-21 expressions in irinotecan-sensitive group and resistant group were 1.09 (95%CI:0.65-1.54) and 4.94 (95%CI:2.44-7.44)(P<0.001), respectively. The plasma miR-21 expressions in irinotecan-sensitive group and resistant group were 1.86 (95%CI:1.08-2.64) and 12.42 (95%CI:3.14-21.70)(P=0.001). Conclusion:A signiifcant correlation was observed between plasma and tumor miR-21 level. The low plasma miR-21 level could benefit from treatment with irinotecan. And low tumor miR-21 expression correlated with increased irinotecan and cisplatin response rate.

Comparison between Therapeutic Efficacies of Histone Deacetylase Inhibitors and Established Drug Regimens Against Breast Cancer Cells using the Histoculture Drug Response Assay / 한국유방암학회지

PURPOSE: Histone deacetylase inhibitors (HDACIs) induce accumulation of acetylated histones in nucleosomes, which lead to reactivate gene expression and inhibit the growth and survival of tumor cells. This study evaluated the efficacy of HDACIs in breast cancer cells in comparison with other established drug regimens. METHODS: Drug responses of tumor samples from mastectomy specimens of 78 breast cancer patients were evaluated using the histoculture drug response assay (HDRA). Tumor inhibition rates (IRs) of established drug regimens such as doxorubicin, cyclophosphamide, doxorubicin with cyclophosphamide (AC), paclitaxel, docetaxel and doxorubicin with docetaxel (AT), as well as those of three HDACIs (SAHA, PXD101, and a novel compound CG-2) were evaluate. RESULTS: The percentages of chemosensitive tumors (chemoresponsiveness) were 26.9-60.3% with established regimens and 61.5-73.1% with HDACIs when the cutoff value for inhibition rate was set at 30%. Breast cancer cells appeared to be more chemoresponsive to HDACIs than to established drug regimens. Chemoresponsiveness to AT was the highest among the established drug regimens. A combination regimen offered higher activity than did a single drug (doxorubicin vs AT; p<0.001). HER2/Neu-overexpressing breast cancers were chemosensitive to SAHA and AT (p=0.031 and 0.04, respectively). CONCLUSION: Our findings show that breast cancer cells were sensitive to HDACIs, with therapeutic efficacies comparable to those of established drug regimens. Specific biological markers such as HER2/Neu could be assessed for effectiveness as HDACIs chemosensitivity markers in further clinical trials.

Can the Histoculture Drug Response Assay Predict the Clinical Results of Chemotherapy in Breast Cancer? / 한국유방암학회지

PURPOSE: The behavior of invasive carcinomas in human can be very varied with different individual responses to chemotherapy. Individualization is crucial to the optimization of chemotherapy. Therefore, the prediction of a tumor's sensitivity to anticancer agents has been the subject of intensive investigation. In order to investigate the pathobiology of breast cancer, it is necessary to maintain or recreate the characteristics of the three-dimensional architecture of the tissues in culture. In this study, we have evaluated the relationship between the Histoculture Drug Response Assay (HDRA) assessment and chemotherapy responses in breast cancer patients. METHODS: Tumor specimens from 30 patients with breast cancer were evaluated using the HDRA. Tumor tissues were cultured on gelfoam sponge gel in 24-well plates, followed by treatment with a variety of chemotherapeutic agents. All treatments were conducted in triplicate. The sensitivity of a chemotherapy regimen was defined as a tumor inhibition rate (IR) in excess of 30%. Neoadjuvant or palliative chemotherapy for patients, using anthracycline or taxane, was conducted on the basis of the established protocols. The responses to treatments were compared with the results of the HDRA. RESULTS: The mean IR for the combinations of doxorubicin and docetaxel and for FAC and AC were 48, 45, and 36%, respectively. The above partial rate of response to chemotherapy was 81.1%. The sensitivity and specificity of the HDRA assessment, with a 30% inhibition rate, were 81.5 and 66.7%, respectively. The positive and negative response prediction values were 91.7 and 44.4%, respectively. The responses to treatments and the results of the HDRA assessment were not correlated with the expressions of the hormonal receptor or c-erbB2. CONCLUSION: In cases in which the inhibition rate is in excess of 30%, the HDRA assessment yielded a high positive response prediction value. The sensitivity to chemotherapy, as determined by the HDRA, appears to be a good guide for selection in breast cancer patients. Thus the results presented herein should be integrated into future research on the subject.

Can the Histoculture Drug Response Assay Predict the Clinical Results of Chemotherapy in Breast Cancer? / 한국유방암학회지

PURPOSE: The behavior of invasive carcinomas in human can be very varied with different individual responses to chemotherapy. Individualization is crucial to the optimization of chemotherapy. Therefore, the prediction of a tumor's sensitivity to anticancer agents has been the subject of intensive investigation. In order to investigate the pathobiology of breast cancer, it is necessary to maintain or recreate the characteristics of the three-dimensional architecture of the tissues in culture. In this study, we have evaluated the relationship between the Histoculture Drug Response Assay (HDRA) assessment and chemotherapy responses in breast cancer patients. METHODS: Tumor specimens from 30 patients with breast cancer were evaluated using the HDRA. Tumor tissues were cultured on gelfoam sponge gel in 24-well plates, followed by treatment with a variety of chemotherapeutic agents. All treatments were conducted in triplicate. The sensitivity of a chemotherapy regimen was defined as a tumor inhibition rate (IR) in excess of 30%. Neoadjuvant or palliative chemotherapy for patients, using anthracycline or taxane, was conducted on the basis of the established protocols. The responses to treatments were compared with the results of the HDRA. RESULTS: The mean IR for the combinations of doxorubicin and docetaxel and for FAC and AC were 48, 45, and 36%, respectively. The above partial rate of response to chemotherapy was 81.1%. The sensitivity and specificity of the HDRA assessment, with a 30% inhibition rate, were 81.5 and 66.7%, respectively. The positive and negative response prediction values were 91.7 and 44.4%, respectively. The responses to treatments and the results of the HDRA assessment were not correlated with the expressions of the hormonal receptor or c-erbB2. CONCLUSION: In cases in which the inhibition rate is in excess of 30%, the HDRA assessment yielded a high positive response prediction value. The sensitivity to chemotherapy, as determined by the HDRA, appears to be a good guide for selection in breast cancer patients. Thus the results presented herein should be integrated into future research on the subject.

Histoculture Drug Response Assay in Colorectal Cancer Specimen

PURPOSE: For decades, systemic medical treatment for colorectal cancer has been limited almost entirely to 5- fluorouracil (5-FU). In cases of advanced colorectal cancer, the response rate to standard 5-FU regimen was lower than 20%. Recently, new drugs that have another action mechanism have been introduced-irinotecan, oxaliplatin, raltitrexed, capecitabine, etc. Clinicians have to choose the appropriate drug for advanced cases. Until recently, choice of chemotherapeutic agents was based on the experience of clinicians, or on retrospective or prospective clinical trial reports. In this study, we performed HDRA (histoculture drug response assay) to assess the effectiveness of chemotherapeutic agents in colorectal cancer. METHODS: Tumor specimens of 33 colorectal cancers were collected in 15 ml tubes containing PBS buffer. Tissues were minced using an autoclaved knife and histocultured on collagen sponge gel matrix, followed by treatment with 5-FU, 5-FU & leucovorin, oxaliplatin, oxaliplatin & 5-FU, irinotecan, or irinotecan & 5-FU. After 48 hours, cell viability was assessed by MTT assay. The inhibition rate of each drug was calculated for relative survival. Cases of drug responsibility below 30% were regarded as drug resistant cases. RESULTS: Thirty cases were tested. Three cases had synchronous lesion. Thirty-three tissues were evaluated using HDRA. Seventeen cases (53.3%) were rectal cancer. The initial 6 cases were tested using a single agent the other 27 cases were tested using combined agents. The regimen showing the best responses was oxaliplatin with 5-FU (8/26 cases, 30.8%). Seven cases were regarded as chemoresistant cases because they showed low IR below 30% for all agents. Synchronous lesions showed similar drug responses. CONCLUSION: HDRA is relatively simple and easily applicable to in vitro study to determine the appropriate chemotherapeutic agents. Further study is necessary to assess the effectiveness including tumor recurrence and survival.