Antitumor effect of TAT-oxygen-dependent degradation-caspase-3 fusion protein specifically stabilized and activated in hypoxic tumor cells

Human solid tumors contain hypoxic regions that have considerably lower oxygen tension than normal tissues. These impart resistance to radiotherapy and anticancer chemotherapy, as well as predisposing to increased tumor metastases. To develop a potentially therapeutic protein drug highly specific for solid tumors, we constructed fusion proteins selectively stabilized in hypoxic tumor cells. A model fusion protein, oxygen-dependent degradation (ODD)-beta-galactosidase (beta-Gal), composed of a part of the ODD domain of hypoxia-inducible factor-1alpha fused to beta-Gal, showed increased stability in cultured cells under a hypoxia-mimic condition. When ODD-beta-Gal was further fused to the HIV-TAT protein transduction domain (TAT(47-57)) and i.p. injected to a tumor-bearing mouse, the biologically active fusion protein was specifically stabilized in solid tumors but was hardly detected in the normal tissue. Furthermore, when wild-type (WT) caspase-3 (Casp3(WT)) or its catalytically inactive mutant was fused to TAT-ODD and i.p. injected to a tumor-bearing mouse, the size of tumors was reduced by the administration of TAT-ODD-Casp3(WT) but not by TAT-ODD-mutant Casp3. TAT-ODD-Casp3(WT) did not cause any obvious side effects on tumor-bearing mice, suggesting specific stabilization and activation of the fusion protein in the hypoxic tumor cells. These results suggest that the combination of protein therapy using a cytotoxic TAT-ODD fusion protein with radiotherapy and chemotherapy may provide a new strategy for annihilating solid tumors.     

Breast cancer

Adjuvant chemo-endocrine therapy for breast cancer (ACETBC) trial has been the first large scaled clinical trial performed in Japan. Several prospective randomized trials have been performed in Japan since ACETBC-1 trial started in 1985. The effect of oral 5-FU agents had been tested in prospective randomized trials and the statistically marginal effect of oral 5-FU agents in adjuvant settings has been reported. Several trials having CMF as a control arm started in 1996 when CMF combination chemotherapy was approved by the government. The results of these trials have not been published. To perform good clinical trials, it is imperative to construct infrastructures including clinical research coordinator, and abolish governmental regulation of the dose of anticancer agents.     

Current status of the chemotherapy for lung cancer

In the treatment of limited-stage small cell lung cancer (LD-SCLC) and unresectable locally-advanced non-small cell lung cancer, several phase III trials and meta-analysis have demonstrated the following: 1) combining chemotherapy and thoracic irradiation is better than chemotherapy alone or radiotherapy alone, 2) the concurrent use of chemoradiotherapy has been expected a better survival than the sequential use, 3) the improvement in outcome seen with a concurrent chemoradiotherapy approach may be because of spatial cooperation, enhanced radiosensitization, and/or enhanced cytotoxicity, and 4) the chemoradiotherapy is tolerable without significant morbidities, such as pneumonitis and esophagitis. However, the chemoradiotherapy is still an investigational strategy because of the absence of a definite schedule and dose on radiotherapy. Newer, more tolerable chemotherapeutic agents, molecular biologic novel approaches and newer irradiated procedures are now being investigated.     

Combination chemotherapy with carboplatin and etoposide for elderly patients aged 76 years or older with small cell lung cancer

Eighteen elderly patients aged 76 years or older with small cell lung cancer were treated with carboplatin (AUC = 4 mg/ml.min, i.v. day 1) and etoposide (70 mg/m2 i.v. day 1-3) and 17 patients were evaluable. The median age of the study population was 77 years (range: 76-81). Eight patients had limited disease (LD) and nine did extensive disease (ED). The overall response rate was 88% for LD patients and 67% for ED patients. Median survival time was 219 days for LD patients and 158 days for ED patients. Grade 3 and 4 leukopenia, neutropenia, thrombocytopenia and anemia occurred in 41%, 76%, 24% and 6% of patients, respectively. There was one treatment-related death due to pneumonitis.     

A case of gastric cancer with multiple liver metastases responding to TS-1

We report the case of a 58-year-old male with Stage IV gastric cancer accompanied by multiple liver metastases, which responded to chemotherapy using TS-1. The patient was treated with daily oral administration of 120 mg TS-1 for 4 weeks followed by 2 weeks rest as 1 cycle. After 4 cycles, most of the liver metastases had disappeared and serum CEA level was reduced from 140 to 53.9. The patient received chemotherapy at our outpatient clinic for 9 months during which time there was no regrowth after the first treatment. The current case suggests that TS-1 may have a potent therapeutic efficacy in cases of advanced gastric cancer.     

A case report of both CAF and docetaxel-resistant breast cancer responding to paclitaxel weekly therapy

A 58-year-old woman underwent CAF and docetaxel therapy for lung, liver and bone metastases from breast cancer operated on 14 years ago. Because of progressive disease due to secondary resistance to CAF and docetaxel, the patient was given three courses of paclitaxel therapy (60 mg/m2, day 1, 8, 15, repeated every 4 weeks). The paclitaxel weekly therapy brought about no adverse effects and remarkable effects against lung and liver metastases (PR). Although the duration of the response to the paclitaxel therapy was limited to about two months due to the progression of skull bone metastasis, paclitaxel weekly therapy may be effective against both CAF and docetaxel-resistant breast cancer.