Activity of docetaxel in paclitaxel-resistant ovarian cancer cells

Purpose The aim of this study was to determine the behavior of docetaxel (DTX) in ovarian cancer cells resistant to paclitaxel (PTX).Methods We used human ovarian adenocarcinoma cell lines KF, KFTx (PTX-resistant KF), SK-OV-3, and HAC-2. The sensitivity of the cells to PTX or DTX was determined by the MTT assay. Cellular accumulation of PTX and DTX was measured by high-performance liquid chromatography. mRNA of MDR-1 was detected by RT-PCR. Cell cycle distribution was determined by flow cytometry after exposure to the IC₅₀ of each drug. Bcl-2 phosphorylation was determined by Western blot analysis. Activity for tubulin polymerization of each drug was examined by a -tubulin polymerization assay.Results KFTx cells had a 5.5-fold greater resistance to PTX and a 7.3-fold greater resistance to DTX than KF cells, indicating that KFTx cells had acquired cross-resistance to DTX. SK-OV-3 cells were sensitive and HAC-2 cells were resistant to both PTX and DTX. The gene expression of MDR-1 increased after exposure to DTX in KF and KFTx cells. Residual cellular accumulation of PTX and DTX was significantly lower in KFTx cells than in KF cells. In contrast, MDR-1 expression was not detected in SK-OV-3 and HAC-2 cells. Flow cytometric analysis indicated no differences in alterations of cell cycle distribution following exposure to the two drugs. Bcl-2 phosphorylation occurred after exposure to DTX at a concentration equivalent to the clinical dose, but did not occur after exposure to PTX in KFTx cells. In HAC-2 cells, Bcl-2 phosphorylation was not detected after exposure to DTX or PTX at concentrations equivalent to the clinical doses. DTX showed greater tubulin polymerization activity than PTX in KFTx cells. -tubulin polymerization did not correlate with the concentration of PTX or DTX, suggesting that alteration in the tubulin reaction might contribute to the resistance in HAC-2 cells.Conclusions The present study suggests that the mechanisms involved in cytotoxicity of and resistance to PTX and DTX do not differ, but DTX has a greater cytotoxic potential in PTX-resistant cells with an efflux system.     

Phase I trial of carboplatin and weekly paclitaxel in patients with advanced non-small-cell lung cancer

OBJECTIVE: This study was designed to determine the maximum tolerated dose of paclitaxel administered weekly in combination with carboplatin and to assess its dose limiting toxicity and preliminary activity in patients with previously untreated, advanced non-small-cell lung cancer. METHODS: Carboplatin was administered at a fixed dose that maintained an area under the curve of 6. Paclitaxel was given over 1 h once a week for 3 weeks starting at 60 mg/m(2) and escalated in 10 mg/m(2) increments. RESULTS: Twenty-one patients were treated with six dose levels (60, 70, 80, 90, 100, 110 mg/m(2)) of paclitaxel. The dose limiting toxicity was infection and the maximum tolerated dose was 110 mg/m(2). Nine of 21 (42.9%) patients demonstrated a therapeutic response. CONCLUSION: Weekly paclitaxel and carboplatin were well tolerated. Based on our results, 100 mg/m(2) of paclitaxel for 3 weeks of a 4-week cycle, in combination with carboplatin, was recommended for a phase II study.     

A case of advanced gastric cancer effectively treated by combined chemotherapy of paclitaxel (TXL) and CDDP

The patient was a 73-year-old man with unresectable advanced gastric cancer and celiac and supraclavicular lymph node metastases. Neoadjuvant chemotherapy consisting of paclitaxel (TXL) and CDDP was administered. TXL (80 mg/m2) and CDDP (25 mg/m2) was administered weekly on day 1, 8 and 15 as 1 cycle. After 4 cycles of TXL/CDDP administration, the lymph node metastases and gastric tumor had decreased almost completely in size and distal partial gastrectomy was performed. After surgery, the patient was treated with 4 courses of TXL/CDDP and has survived without recurrence to the present. TXL/CDDP is associated with few adverse events in hospital visits, and is thought to be an effective chemotherapy against advanced gastric cancer.     

In vitro chemosensitivity test for hepatocellular carcinoma using collagen-gel droplet embedded cultures

This study evaluated an in vitro assay for chemosensitivity test using a collagen-gel droplet-embedded culture drug sensitivity test (CD-DST) for hepatocellular carcinoma (HCC). In 25 patients with HCC, in vitro chemosensitivity to 5-fluorouracil (5-FU), epirubicin (EPI), and cisplatin (CDDP) was examined by CD-DST, and 5-FU, EPI, and paclitaxel (PTX) were examined in 38 patients with breast cancer. Successful rates of chemosensitive evaluation by CD-DST were 64% for HCC and 79% for breast cancers. Although chemosensitivities of breast cancer were 5-FU 23.1%, EPI 83.3%, and PTX 67.7%, only one HCC sample was sensitive to EPI. Growth rates of HCC for 7 days of culture were significantly lower than those of breast cancers (1.04 vs 3.61). The culture methods for HCC in CD-DST should be improved to estimate accurate results.     

Indication and limitation of endoscopic surgery against urological cancer

Endoscopic surgery in the urological field begins with cystoscopy and transurethral resection, and it develops into laparoscopic surgery. The indication of laparoscopic surgery for a malignant tumor also gradually expands. It is virtually impossible to search for urological cancer using laparoscopic procedures. In particular, out laparoscopic nephrectomy for renal cancer and transurethral resection for bladder cancer used widely in Japan. In the future, laparoscopic partial nephrectomy and the laparoscopic procedure for adrenal cancer and prostate cancer are considered to become widespread.     

Pancreatic Cancer Registry in Japan: 20 years of experience

The prognosis of pancreatic cancer is defined by the histology and extent of disease. Preoperative histologic diagnosis and diagnostic imaging are fundamentals in managing the disease, but it is not rare to find unexpected peritoneal dissemination or liver metastasis at the time of operation. The overall resectability rate of pancreatic cancer is 40% in Japan. Resecting the portal vein and peripancreatic plexus were performed on 40% of the patients who underwent pancreatectomy for invasive cancer in the head of the pancreas. Long-term survival was only found in patients who underwent pancreatectomy. Radical lymph node dissection, or combined resection of the large vessels, did not seem to improve survival further than the standard resection. Multidisciplinary treatments combined with surgery were performed, and various effects of postoperative chemotherapy after pancreatectomy, intraoperative- and postoperative-radiation therapy, or postoperative chemotherapy for unresectable tumor, were shown. Development of unconventional therapies and refinement of the conventional therapy should be promoted on a randomized prospective trial basis. To promote this effort, which requires the international comparisons and cooperation, JPS developed a computerized JPS registration system downloadable from the JPS website (http://www.kojin.or.jp/suizou/index.html).     

A case of pseudoaldosteronism, accompanied with hypocalcemia and exaggerated ACTH response

Glycyrrhizic acid (GA) inhibits the activity of 11beta-hydroxysteroid dehydrogenase type 2 in the kidney, with the resulting increase in intrarenal cortisol concentration leading to hypertension and suppression of the renin-aldosterone system. In this paper we describe an interesting case of pseudoaldosteronism, associated with hypocalcemia and an exaggerated ACTH response. A 72-year-old woman was referred to our department for further evaluation of hypokalemia and hypocalcemia. The patient had been taking GA (150 mg/day) for the previous year for treatment of liver damage. Plasma renin activity and aldosterone concentration were both within lower normal limits. Urinary excretion of potassium and calcium was within the upper limit of the normal range and increased with administration of supplements. Plasma ACTH levels increased markedly in response to an intravenous injection of CRH. Cessation of GA and the potassium and calcium supplements on admission, led to a gradual normalization of serum potassium and calcium levels and blood pressure. The hypocalcaemia in our patient was related to decreased tubular reabsorption of calcium as a consequence of renal corticoid excess. It is possible that an increase in the number of CRH receptors in the pituitary following GA treatment caused the exaggerated ACTH response in association with pseudoaldosteronism. The existence of hypocalcemia and an exaggerated ACTH response should be observed carefully when managing pseudoaldosteronism.     

Bilateral Bowen's disease

Multiple Bowen's disease may be difficult to differentiate from bowenoid papulosis because of its clinicopathological resemblance to bowenoid papulosis. We experienced a case of bilaterally and symmetrically developed multiple bowenoid lesions in a 71-year-old man previously diagnosed as having chronic lymphocytic lymphoma (CLL). Based on histological findings and the results of human papillomavirus examinations, we finally diagnosed this case as bilateral Bowen's disease. We speculate that the underlying immunosuppressive state due to CLL may have been associated with onset of the disease. We report the unique clinical picture, the differential diagnosis and the aetiology.     

Intraventricular transplantation of embryonic stem cell-derived neural stem cells in intracerebral hemorrhage rats

In the present study, we attempted to explore cell transplantation therapy for intracerebral hemorrhage (ICH) using embryonic stem (ES) cells. Collagenase-induced ICH rats were used as model animals. Mouse ES cells were differentiated into nestin-positive neural stem cells in vitro by alltrans retinoic acid (ATRA). ATRA-treated ES cells (10(5)) were transplanted into the lateral ventricle in the hemisphere contralateral to the hemorrhage 7 days after collagenase infusion. Twenty-eight days after transplantation, ES-derived neurons and astrocytes were observed around the hematoma cavities of the brain in all of the ten rats receiving grafts. Graft-derived neurons were found in the subependymal area of the lateral ventricle as cellular nodules. Although one of the ten rats receiving grafts showed uncontrolled growth of astroglia derived from the ES cells, intraventricular transplantation of ATRA-treated ES cells is an effective delivery system of neuronal lineage-committed progenitor cells toward the site of ICH.