CDDP Combination Chemotherapy Research Articles

HIF-1\u03b1-dependent miR-424 induction confers cisplatin resistance on bladder cancer cells through down-regulation of pro-apoptotic UNC5B and SIRT4

BackgroundChemo-resistance of bladder cancer has been considered to be one of the serious issues to be solved. In this study, we revealed pivotal role of miR-424 in the regulation of CDDP sensitivity of bladder cancer cells.MethodsThe cytotoxicity of cisplatin and effect of miR-424 were assessed by flow cytometry and TUNEL. Transcriptional regulation of miR-424 by HIF-1α was assessed by Chromatin immunoprecipitation (ChIP). Effect of miR-424 on expression of UNC5B, SIRT4 (Sirtuin4) and apoptotic markers was measured by QRT-PCR and/or Western blot. The regulation of miR-424 for UNC5B and SIRT4 were tested by luciferase reporter assay. The 5637-inoculated nude mice xenograft model was used for the in vivo study. The clinical significance of miR-424 was demonstrated mainly through data mining and statistical analysis of TCGA.ResultsIn this study, we have found for the first time that cisplatin (CDDP) induces the expression of miR-424 in a HIF-1α-dependent manner under normoxia, and miR-424 plays a vital role in the regulation of CDDP resistance of bladder cancer cells in vitro. Mechanistically, we have found that UNC5B and SIRT4 are the direct downstream target genes of miR-424. CDDP-mediated suppression of xenograft bladder tumor growth was prohibited by the addition of miR-424, whereas ectopic expression of UNC5B or SIRT4 partially restored miR-424-dependent decrease in CDDP sensitivity of bladder cancer 5637 and T24 cells. Moreover, knockdown of UNC5B or SIRT4 prohibited CDDP-mediated proteolytic cleavage of PARP and also decreased CDDP sensitivity of these cells. Consistently, the higher expression levels of miR-424 were closely associated with the poor clinical outcome of the bladder cancer patients. There existed a clear inverse relationship between the expression levels of miR-424 and pro-apoptotic UNC5B or SIRT4 in bladder cancer tissues.ConclusionsCollectively, our current results strongly suggest that miR-424 tightly participates in the acquisition/maintenance of CDDP-resistant phenotype of bladder cancer cells through down-regulation of its targets UNC5B and SIRT4, and thus combination chemotherapy of CDDP plus HIF-1α/miR-424 inhibition might have a significant impact on hypoxic as well as normoxic bladder cancer cells.

Surgical treatment of scirrhous gastric carcinoma

Scirrhous gastric carcinoma is a special type of gastric carcinomas and accompanied with highly interstitial fibrosis and diffuse cellular infiltration. Scirrhous gastric carcinoma is mainly composed of poor-differentiated adenocarcinoma and signet-ring cell carcinoma, with the clinical features of Borramann 4, thickening and stenosis of stomach wall, high peritoneal and lymph node metastases rates and poor prognosis. R0 resection and postoperative chemotherapy with S-1 as a main way are necessary for the patients who are able to undergo curable resection. The palliative operation should be applied to patients with ileus and urinary obstructions caused by peritoneal metastasis because of limited effect of surgical treatment. Chemo-therapy is the best choice for patients who are not able to undergo curable resection, conversional therapy can improve the prognosis of patients, and preoperative S-1/CDDP combination chemotherapy is an expectable therapy. Moreover, controlling peritoneal metastasis and effect of intraperitoneal chemotherapy are much anticipated. The efficiency of molecular targeted therapy by bevacizumab and gene therapy by adenovirus remain further study. Key words: Gastric neoplasms, scirrhous; Surgical procedures, operative; Chemotherapy

腸瘻からのS-1＋CDDP療法で切除可能となった進行胃癌の１例

腸瘻からのS-1＋CDDP療法で切除可能となった進行胃癌の１例

A Case of Advanced Gastric Cancer with Liver Metastases Resected Successfully after S-1+CDDP Combination Chemotherapy

症例は63歳男性. 上腹部不快感を主訴に近医を受診した. 上部消化管内視鏡検査で胃前庭部小弯に, 2型の腫瘍を認め, 生検の結果, 中～低分化管状腺癌と診断され, 石井病院外科に紹介された. CT検査で肝左葉に大きさ約5 cmの低吸収領域を認め, 胃癌の肝転移と診断した. 平成22年4月からS-1＋CDDP療法を開始した. 7コース終了後の内視鏡では腫瘍は明らかに縮小傾向で, 瘢痕組織様であった. またMRIで肝転移の著明な縮小がみられ, 腫瘍は外側区域に限局した. 平成23年3月群馬大学医学部附属病院で幽門側胃切除D2郭清, Billroth I法再建, 肝外側区切除を施行した. 病理学的にはtub2, pT2 (MP), pN0, INFβ, ly0, v2, PM (－), DM (－), H1, pStage IVであったがR0切除ができた. 経過は良好で, 第12病日に退院した. その後石井病院外来で経過観察中であるが, 術後5ヶ月の現在明らかな再発はない.

Efficacy of Unresectable or Recurred Gastric Cancer Treated with TS-1 Chemotherapy or TS-1/CDDP Combination Chemotherapy

Purpose：Although several chemotherapy regimens used against advanced and recurred gastric cancer have been studied extensively in an attempt to further improve the prognosis of patients, no standard chemotherapeutic regimens have been established. The aim of this study was to determine the anti-tumor efficacy and safety of TS-1 or TS-1 plus cisplatin (CDDP). Materials and Methods：From December 2004 to June 2007, we treated 43 patients with unresectable or recurred gastric cancer either with 80 mg/m2 of TS-1 for 28 days, which was followed by a 2-week rest, or with 80 mg/m2 of TS-1 for 28 days and 60 mg/m2 of CDDP on day 3 every 6 weeks. Results：Tumor response rates in the primary chemotherapy group and in the recurrent group were 46.7% and 21.4%, respectively. The median survival rates in the primary and the recurrent group were 14 months and 8 months, and it was not significantly different. But the one-year survival rates according to the kinds of regimens (TS-1 or TS-1/CDDP group) were significantly different (P=0.0014). The incidences of grade 3 or 4 adverse effects were 18%, respectively. Conclusion：The anti-tumor efficacy and safety of TS-1 and TS-1 plus CDDP in unresectable or recurred gastric cancer patients seemed to be high with modest adverse effects, thus suggesting the possible use of this regimen for unresectable or recurred gastric cancer patients.

POS-02.34: Clinical trial of metastatic bladder carcinoma treated by S-1/CDDP combination chemotherapy

Prognosis of advanced transitional cell carcinoma (TCC) of the bladder after first-line chemotherapy is poor and difficult to treat. And the chemotherapy for metastatic non-TCC of the bladder hasn’t been established. To assess the antitumor activity and toxicity of S-1/CDDP combination chemotherapy as second-line treatment in patients with advanced TCC of the bladder and as first-line chemotherapy in patients with non-TCC of the bladder.

High-Grade Papillary Cystadenocarcinoma of the Sublingual Gland: A Case Report

Tumors arising in the sublingual glands are rare, and most of these tumors are malignant neoplasms. Papillary cystadenocarcinoma of the salivary glands is an uncommon lesion with low-grade histological and clinical features. It accounts for less than 0.2% of all salivary gland tumors and was first classified as a distinctive neoplasm in 1991 by the World Health Organization (WHO). 1 Histologically, this neoplasm shows cysts and papillary endocystic projections characteristically. 1 Foss et al reported that there were 57 cases of papillary cystadenocarcinoma of the salivary gland, according to the files of the Armed Forces Institute of Pathology (AFIP). 2 In these cases, 35 originated in the parotid gland, and 20 cases originated in the minor salivary glands. Only 2 cases arose in the sublingual gland in their study. This article describes an extremely rare case of high-grade papillary cystadenocarcinoma of the right sublingual gland, which was effectively treated for recurrence after segmental resection of the mandible and total neck dissection with TS-1 and low-dose CDDP combination chemotherapy.

Our experience of low-dose consecutive CDDP and intermittent S-1 (LP/IS) therapy for advanced gastric cancer

14145 Background: 5-FU and CDDP combination chemotherapy (FP) has been widely used as standard therapy for advanced gastric cancer (AGC), and in Japan FP therapy was modified into [5-FU (CVI) and low-dose consecutive CDDP (LC-P)](LFP) Therapy from 1990. LFP therapy has been widely used for the treatment of AGC, because of low toxicity and high response rate. We observed that CDDP inhibited metionine transport into tumor cells, both in vitro and in vivo, with synergistic interaction by CDDP functioning as a modulator of 5-FU. However LFP Therapy needs 24-hour continuous infusion of 5-FU, the applicants for LFP must be hospitalized. Therefore we used S-1, novel oral fluoropyrimidine as effector of 5-FU, and combined LC-P aiming the same synergy as LFP therapy. In addition, utilizing the difference in cell cycle between normal cells and tumor cells, we applied intermittent administration of S-1, which leads lower toxicity than conventional LFP therapy. We tried this LC-P and intermittent S-1 (LP/IS) Therapy for AGC, examining whether LP/IS was possible as outpatient-basis. Methods: Patients with AGC received LP/IS therapy. S-1 (80 mg/m2/day) was administered per orally and CDDP (10 mg/body/day) was infused for half an hour. The administration schedule consisted of S-1 for 1,3,5 days intermittently and CDDP for 2,5 days twice a week for each four weeks. RESIST criteria and NCI-CTC (ver.3) were used to assess LP/IS. Results: Between July and November 2005, four patients (A/B/C/D) were entered into this trial. Information is available for all patients. Characteristics were: age (A/B/C/D=75/59/65/54): sex (A/B/C=M, D=F): disease status (A/B= locally advanced, C/D= postoperative recurrence). S-1 and CDDP were administered to 97.9% and 84.4% of planned dose, respectively. As for toxicity, only grade 2 taste disturbance and anorexia occurred in two patients. All the patients had one course LP/IS and are evaluable for anti-tumor effects; primary (A/B=NC/NC), metastatic (A/B/C/D=NC/NC/NC/PD), respectively. A and B could undergo total gastrectomy. TTF was (A/B/C/D=42/35/55/29 days), and survival time was (A/B/C/D=164/94/104/71 days, C: dead). Conclusions: Because of low toxicity and high feasibility, LP/IS therapy is appropriate for out-patient basis chemotherapy for AGC. No significant financial relationships to disclose.

Combination chemotherapy with estramustine phosphate, ifosfamide and cisplatin for hormone-refractory prostate cancer.

We evaluated the efficiency and toxicity of estramustine phosphate (ECT), ifosfamide (IFM) and cisplatin (CDDP) combination chemotherapy in twenty-one patients with hormone-refractory prostate cancer (HRPC), for which there is currently no effective treatment. Patients received a daily dose of 560 mg ECT in combination with 1.2 g/m2 IFM on days 1 to 5 and 70 mg/m2 CDDP on day 1. This combination therapy was given every 3 to 4 weeks. An objective response of more than 50% reduction in prostate-specific antigen was observed in 9 of 18 patients (50%), and a more than 50% reduction in bi-dimensionally measurable soft-tissue lesions was observed in 2 of 7 patients (29%). The median duration of response among the cases showing partial response was 40 weeks, while the median duration of response of overall partial-response plus stable cases was 30 weeks. The median survival duration of all cases was 47 weeks. Toxicity was modest and acceptable. In conclusion, the ECT, IFM and CDDP combination chemotherapy regimen is a viable treatment option for HRPC. However, in comparison with our previous chemotherapy regimen of IFM and CDDP, no additional long-lasting effects resulting from the inclusion of ECT could be affirmed.

A phase II study of 5-FU (CVI) and low-dose consecutive CDDP (LFP) therapy in advanced gallbladder carcinoma

4261 Background: Unresectable and recurrent gallbladder carcinoma (GBca) are known to be poor prognosis. In Japan 5-FU alone or modified FAM therapy was once tried to these malignancies, but no objective response was aquired. By the way, 5-FU and CDDP combination chemotherapy (FP) has been widely used as standard chemotherapy for gastrointestinal cancer, and in Japan FP therapy was modified into 5-FU (CVI) and low-dose consecutive CDDP (LFP) Therapy from 1990. Because of low toxicity and relatively high response rate, LFP therapy has been widely used for the treatment of gastrointestinal cancers in Japan. We are conducted a single arm phase II study of LFP therapy in patients with advanced GBca. Methods: Patients with advanced or recurrent bile duct carcinoma received LFP therapy. 5-FU (160mg/m2/day) was continuously infused over 24 hours using an implantable port and CDDP (3mg/ m2/day) was infused for half an hour. The administration schedule consisted of 5-FU for 7 consecutive days and drip infusion of CDDP twice a week for each four weeks according to response and tolerance. RESIST criteria was used to assess tumor response. The toxicity was estimated by NCI-CTC (ver.3). Median survival time (MST) and median time to treatment failure (TTF) was calculated by the Kaplan-Meier method. Results: Between May 1996 and September 2003, 13 patients were entered into this trial. Information is available for all patients. Characteristics were: mean age 69.4±5.0: male 6: locally advanced 10, postoperative recurrence 3. Overall, most common toxicity was appetite loss occurring 38.5% of patients. Hematological toxicity (up to grade 2) was occurring in 23.1% of patients. No grade 4 toxicity occurred. All the patients are evaluable for effects with an over all response rates of 46.2% (6 PR, 2 NC, 5 PD). Estimated MST is 150 days. 1-year and 2-year survival rate were 16.8% and 0.0%, respectively. Estimated median TTF is 85 days. Conclusions: This study resulted in high response rate and tolerable adverse effect. This outpatient-basis LFP therapy promises to advance the quality of life of the cancer patients and to be useful in the clinical management of advanced or recurrent GBca tract malignancy for first line chemotherapy. No significant financial relationships to disclose.

A phase I/II study of S-1 plus cisplatin (CDDP) in patients with head and neck cancer (HNC)

5552 Background: S-1 is an active anticancer drug for HNC with a response rate of 28.8% as single agent treatment in phase II study (#1526, 2001ASCO). It has also shown synergistic effects with CDDP in a preclinical study. The aims of this study was to determine the maximum tolerated dose (MTD) and recommend dose (RD) in the combination treatment with S-1 and CDDP (Phase I part), and evaluate the response and safety using defined RD (Phase II part). Methods: Eligible patients were defined as histologically or cytological confirmed advanced/recurrent HNC with evaluable lesions, adequate organ function, Performance Status 0–1, age < 80. S-1 was administered orally at 40mg/sqm twice a day for 14 consecutive days, and CDDP (Level.1–2:60–70mg/sqm, within approved dose in JPN) was infused over 2 hours on day 8. Each course was repeated every 3–4 weeks. Dose limiting toxicities (DLT) were determined as grade 4 hematological and grade 3 non-hematological. Results: A total of 38 patients, 10 patients for Phase I and additional 28 patients for Phase II part, were registered. Although DLT was not observed in Level.1 (n=4), fatigue and diarrhea of grade 3 (DLT) occurred in Level 2(DLT:2/6). MTD was not achieved in Phase I part. Level 2 (70mg/sqm of CDDP) was considered as recommend dose for phase II part. The median number of courses was 2 (range 1–3) in 34 patients. Among these 34 patients, response rate was 67.6% (CR:6, PR:17) at the termination of treatment. Conformed responses with adequate duration time (d28) were 2 complete response and 13 partial responses with an overall response rate of 44.1% (95%CI:27.4–60.8). The degree of toxicity was generally mild to moderate. Hematological toxicities of grades 3 and 4 included neutropenia (11.8%), thrombocytopenia (11.8%) and anemia (8.8%). Non-hematological toxicity of grades 3 and 4 included anorexia (26.5%), nausea (14.7%), fatigue (8.8%) or diarrhea (2.9%).Since the observation period is short the median survival time and the 1-year survival rate is not obtained so far. Conclusions: S-1 plus CDDP combination chemotherapy demonstrated a promising effectiveness for not only advanced but recurrent HNC patients with acceptable toxicity rates. These results warrant further investigations of this regimen. No significant financial relationships to disclose.

Phase I/II study of combination chemotherapy of CDDP and CBDCA in patients with non small cell lung cancer

Phase I/II study of combination chemotherapy of CDDP and CBDCA in patients with non small cell lung cancer

Treatment of head and neck cancer with combination chemotherapy of CDDP and radiotherapy

There have been many reports on the usefuless of chemotherapy involving cisplatin for squamous cell carcinoma of the head neck. Single radiotherapy has also achieved excellent therapeutic results. In the present study, combined treatment involving multiple drug therapy (including cisplatin) and radiotherapy was carried out in 102 previously untreated patients with squamous cell carcinoma of the head and neck. The total efficiency rate of treatment involving cisplatin at a dose of 100mg or more per body weight and an X-ray dose of 40Gy or more was determined, along with assessment of differences among the total efficiency rate during the period of chemotherapy, the efficiency rate in Stages III and IV and the rate of complete regression (CR) for these stages. The patients who underwent the simultaneous, combined treatment showed a better efficiency rate and CR rate than the patients who underwent the single treatment. These results indicate that the simultaneous, combined treatment was more effective than the single treatment from the viewpoint of the main purpose of combined treatment involving chemotherapy and radiotherapy, i.e., treatment of Stage III and IV carcinoma or radical cure.

The synergistic effect mechanism of cisplatin and peplomycin therapy. With special reference to the effect on cell cycle progression.

The synergistic effect mechanism of Cisplatin (CDDP) and Peplomycin (PEP) therapy was studied in terms of its effect on cell-cycle progression.Based on the clinical dosing schedule that CDDP administration was followed by PEP after a 48 hours interval, the combination chemotherapy of CDDP and PEP was performed on Ehrlich ascites carcinoma. As a result, a significant synergistic effect was obtained.After a single administration of CDDP, cell accumulation was first observed in the S phase. After 48 hours, cells accumulated in the G2-M phase, but it was reversible and the original pattern restored 96 hours after the administration. After a single administration of PEP, cell accumulation in the G2-M phase was observed, but it also was reversible and the original pattern restored 48 hours after the administration. On the contrary, irreversible response of a DNA pattern was observed after the combination of CDDP and PEP. The occurrence of debris and decrease in cell number may suggest an induction of intense cytotoxic reaction.One possible mechanism of the synergistic effect of the sequential combination of CDDP and PEP is as follows. Cell accumulation in the G2-M phase is most significant 48 hours after CDDP administration, and PEP, with preferential cytocidal effect on the cells in the G2-M phase, may exert its cytocidal effect more efficiently when it is timely administered. This mechanism may explain the excellent clinical efficacy obtained by combination chemotherapy in which CDDP was administered prior to PEP.