Yasuko Murakawa

A novel germline mutation of the LKB1 gene in a patient with Peutz-Jeghers syndrome with early-onset gastric cancer

The gene responsible for Peutz-Jeghers syndrome (PJS), LKB1 (also called STK11) was mapped to chromosome 19p13.3 and was found to encode a putative serine/threonine protein kinase, LKB1. As only a limited number (∼100) of germline mutations of the gene have been reported, and because the protein function is still unclear, information about LKB1 mutations and their expression should be accumulated to understand the phenotype-genotype correlation of this disease. Here we report a patient with sporadic PJS with early-onset gastric cancer. We found a novel germline frameshift mutation (757-758insT) in the LKB1 gene and a marked reduction in LKB1 protein expression in the carcinoma cells, suggesting that the loss of LKB1 function may have led to the carcinogenesis of the gastric cancer.

FDG PET evaluation of residual masses and regrowth of abdominal lymph node metastases from colon cancer compared with CT during chemotherapy

Fluorine-18-2-deoxy-2-fluoro-D-glucose (F-18 FDG) PET may be more suitable for follow-up after cancer treatment than other morphologic approaches, because it reflects tumor viability. A patient with abdominal lymph node metastases from colon cancer was followed by CT and F-18 FDG PET during chemotherapy. F-18 FDG PET tumor images changed in accordance with the clinical progress, whereas CT findings were relatively unchanged. This case clearly shows the utility of F-18 FDG PET for follow-up during cancer chemotherapy.

Safety Verification Trials of mFOLFIRI and Sequential IRIS + Bevacizumab as First- or Second-Line Therapies for Metastatic Colorectal Cancer in Japanese Patients

Objective: S-1 is effective in sequential combination with irinotecan (IRIS) in treating metastatic colorectal cancer. We conducted a randomized phase II trial of modified leucovorin, fluorouracil and irinotecan (mFOLFIRI) + bevacizumab and sequential IRIS + bevacizumab as first- or second-line therapies. Methods: Sixty metastatic colorectal cancer patients were randomly assigned to receive mFOLFIRI + bevacizumab or sequential IRIS + bevacizumab (7.5 mg/kg of bevacizumab and 150 mg/m2 of irinitecan, and 80 mg/m2/day of S-1 orally from day 3 until day 16 as a 3-week course). The primary endpoint was the safety of each method until week 12, with the secondary endpoint being the comparison of the safety and efficacy of the two methods. Results: The safety of the two treatments was comparable, except that G3 anorexia and diarrhoea were less frequent with sequential IRIS + bevacizumab. The overall response rate was 62% [95% confidence interval (CI) 40.1–79.8] versus 72% (95% CI 50.6–86.2), and progression-free survival was 324 days (95% CI 247–475) versus 345 days (95% CI 312–594) with mFOLFIRI + bevacizumab versus IRIS + bevacizumab, respectively. Conclusion: Sequential IRIS + bevacizumab is a safe and effective method of systemic chemotherapy against metastatic colorectal cancer and is compatible with mFOLFIRI + bevacizumab.

Enhancement of the efficacy of anticancer drugs with electroporation: Successful electrochemotherapy against gastric cancer cell lines in vivo and in vitro

BackgroundThe purpose of this study was to determine whether micropore formation caused by application of an electric current can increase the influx of anticancer drugs across cancer cell membranes with a concomitant increase in dose intensity and, therefore, toxicity to cancer cells.MethodsTwo cell lines, GCIY and KATO III, both established from human gastric cancers, were used as target cells to assess the effects of combining electroporation and anticancer drug therapy. Results were measured as the proliferation of cells to 50% of the value in control mice (IC50).ResultsWhen GCIY cells were used as targets in vitro, the IC50 value for bleomycin was decreased significantly by the electroporation, to 10−4 of the dose for the chemotherapeutic agent alone, and the IC50 values of cisplatin and 5-fluorouracil were decreased to one tenth of their baseline values. In the case of KATO III cells, the IC50 value for bleomycin was reduced by 10−2, but that of cisplatin did not change. The IC50 value for doxorubicin did not change when GCIY cells, showing multidrug resistance, or when KATO III cells, lacking multidrug resistance, were subjected to electroporation. When GCIY cells were transplanted subcutaneously into nude mice, the resultant tumors decreased to a minimum size at 2 weeks after combined treatment with bleomycin and electroporation.ConclusionElectroporation seems to be a promising adjunct to cancer chemotherapy.

Intermittent Withdrawal of Oxaliplatin for Alleviating Neurotoxicity during Oxaliplatin-Based Chemotherapy for Japanese Patients with Inoperable or Metastatic Colorectal Cancer: A Phase 2 Multicenter Study

Oxaliplatin-based chemotherapy is a well-established regimen for patients with inoperable and metastatic colorectal cancer. However, one of the major limitations of oxaliplatin-based chemotherapy is sensory neuropathy. It was previously reported that introduction of intermittent oxaliplatin treatment to an oxaliplatin-based regimen has a significant benefit on efficacy or safety. Here, we prospectively assessed whether efficacy and safety of first-line chemotherapy for advanced colorectal cancer are achieved by introduction of withdrawal of oxaliplatin treatment for a certain period (intermittent oxaliplatin treatment). The primary endpoint of the present study is to assess the progression free survival time on patients treated with chemotherapy (mFOLFOX6 (levofolinate, 5-fluorouracil and oxaliplatin combination therapy) plus bevacizumab or CapeOX (oxaliplatin and capecitabine combination therapy) plus bevacizumab) with intermittent oxaliplatin treatment. Bevacizumab is a humanized anti-vascular endothelial growth factor antibody. Median progression-free survival by the mFOLFOX6 plus bevacizumab with intermittent oxaliplatin treatment or the CapeOX plus bevacizumab with intermittent oxaliplatin treatment were 10.6 months (95% confidential interval [CI], 8.3-13.4 months) or 8.0 months (95% CI, 4.2-16.8 months), respectively. Overall response rate by the mFOLFOX6 plus bevacizumab with intermittent oxaliplatin treatment or CapeOX plus bevacizumab with intermittent oxaliplatin treatment was 55.1% or 42.1%, respectively. Grade 3 or 4 neuropathy was observed in 4.1% or 10.5% of patients treated with mFOLFOX6 plus bevacizumab with intermittent oxaliplatin treatment or CapeOX plus bevacizumab with intermittent oxaliplatin treatment, respectively. Introduction of intermittent oxaliplatin treatment has improved severe neuropathy in mFOLFOX6 plus bevacizumab regimen without reducing treatment efficacy.

Phase II intermittent (or stop and go) l-OHP administration of first-line bevacizumab (BV) plus mFOLFOX6 or CapeOX therapies in Japanese patients with mCRC: The interim report of T-CORE0901.

664 Background: Cumulative sensory neurotoxicity of l-OHP used in standard 1st-line FOLFOX / CapeOX +/- BV therapies in mCRC results in impairment of patients quality of life (QoL) and discontinuation of the treatment. CONcePT trial revealed that intermittent l-OHP use in BV plus FOLFOX7 is safe, keeping efficacy comparing with BV plus FOLFOX7 in which l-OHP is administered until time to treatment failure. But it is unknown that intermittent l-OHP administration is also safe and effective in Japanese pts with mCRC Methods: This trial aims to enroll 65 of Japanese pts with mCRC. Either BV+FOLFOX or BV+CapeOX is selected by decision of physician in charge. In BV+FOLFOX arm, pts receive 6 cycles of BV plus mFOLFOX6 (5 mg/kg of BV, 85 mg/m2 of l-OHP, 200 mg/m2 of I-LV, 400 mg/m2 of 5-FU by rapid IV infusion on day1, and 2,400 mg/m2 of 5-FU 46 hr by continuous IV infusion as a 2 weeks course) and 6 cycles of BV plus sLV5FU2. In BV+CapeOX arm, pts recieve 4 cycles of BV plus CapeOX (7.5 mg/kg of BV, 120 mg/m2 of l-OHP and capecitabine 1,000mg/m2 twice daily, day1 to 14 as a 3weeks course) and 4 cycles of BV+capecitabine. The primary endpoint is progression free survival (PFS) and secondary endpoints are tumor response (RR), overall survival (OS), time to treatment failure (TTF) and frequency of neurotoxicity. RESULTS According the protocol, interim analysis about efficacy and safety was performed at the time the 13th pts was received the treatment for 7 months. Median progression free survival is 290+ days (95% CI 119 - 558 days) and PFS of 9 cases were more than 7 months, which is threshold value. No serious adverse effects were observed in 13 cases. The efficacy and safety evaluation committee recommended continuing the study and the current accrual is 47 cases. CONCLUSIONS This is the interim report of T-CORE0901 trial and the study remains open to accrual with projected enrollment completion in 2012.

Mechanism of Cytotoxic Effects of Taxotere in the K562 Human Premyelocytic Leukemia Line

BackgroundTaxotere, a semisynthetic derivative of Taxol, is known to possess cytotoxic effects on various animal cells.MethodsTo better understand the precise mechanism of this drug action, the human promyelocytic leukemia cell line, K562, and its adriamycin and vincristine resistant sublines, respectively termed K562/ADM and K562/VCR, were used as targets.ResultsThe IC50 for taxotere was almost equal to that for VCR. Due to cross-resistance in the K562/ADM cells, the IC50 value was 42.3 times greater with taxotere, although it was still lower than with ADM and VCR. A much lower cross-resistance was noted with the K562/VCR cells. Assessment of MDR-1 mRNA indicated that expression of the multidrug resistance gene product p-glycoprotein in the cell membrane was partly responsible for the resistance. K562 cells treated with taxotere accumulated in G2M of the cell cycle, and morphologically, cells in metaphase were found to be remarkably increased. This indicates inhibition of mitosis. Unlike vincristine or vinblastine, taxotere enhanced the assembly of tubulin into microtubules in the absence of guanosine triphosphate (GTP). Moreover, microtubule disassembly was inhibited even in the presence of calcium ions.ConclusionThese results suggest that the tubulin equilibrium was shifted towards formation and away from degradation of microtubules that lead to metaphase arrest and eventual cell death. Syntheses of DNA, RNA and protein were not inhibited, and topoisomerases I and II were unaffected. Thus taxotere is an analogue of Taxol, showing a similar mechanism of cytotoxic effect to Taxol on the human K562 leukemia cell line as well as on rodent tumor cell lines.