Optimal dosing schedule in combination therapy with irinotecan and doxifluridine in a human colorectal cancer xenograft model

A combination therapy with CPT-11 and 5-FU/LV has been recently established as a first-line therapy for metastatic colorectal cancer. However, severe adverse effects have also been reported from this combination therapy, and a modality to reduce the adverse effects is desired. 5'-DFUR, a pro-drug of 5-FU, shows less myelotoxicity than 5-FU, and thus it may be a better partner to combine with CPT-11. However, since each drug has the possibility of inducing diarrhea, there is concern about their use in combination therapy. Therefore, in the present study, our aim was to establish an optimal schedule in murine models, which shows no increase in diarrhea but maintains potent antitumor activity. In non-tumor bearing mice, CPT-11 was given i.v. at 100 mg/kg/day q2d x 3, and 5'-DFUR was given p.o. at 172 mg/kg/day daily for 14 days. Each of these doses caused diarrhea in the single treatment. CPT-11 was administered simultaneously or sequentially with 5'-DFUR. With the simultaneously administered schedule, the diarrhea appeared stronger than that found in the CPT-11 single or in the 5'-DFUR single treatment groups. On the other hand, with the sequentially administered schedule the diarrhea was not much stronger than that found in the single agent treatment groups. When CPT-11 and 5'-DFUR administrations were separated by three-day intervals, the diarrhea was not augmented at all. In mice bearing human colorectal cancer COLO 205, the antitumor activity of CPT-11 in the combination with 5'-DFUR was additive in all of the examined schedules. The efficacy in the sequential schedule was the same as in the simultaneous schedule. These results suggest that a sequential administration schedule of CPT-11 and 5'-DFUR would be more tolerable than and equally efficacious to the simultaneous administration schedule. Clinical study of this sequential administration in combination therapy is warranted.     

Endoscopic local ablation therapy (ELAT) for hepatocellular carcinoma--inventive approaches to achieve radical treatment and to expand the indication of ELAT

We introduce some inventive approaches in endoscopic local ablation therapy (ELAT) for patients with hepatocellular carcinoma (HCC). ELAT is applied in cases of HCC when the tumor is smaller than 3 cm on the surface of the liver (smaller than 4 cm with extrahepatic growth), and tumor numbers < or = 3. Appropriate use of the laparoscopic, thoracoscopic and hand-assisted approaches, suitable preceding embolizations with the angiographic technique, a combination of ablation therapy, and the use of CO2-angio US, DIMON puncture system and cluster needle are important. If necessary, additional surgeries such as endoscopic hepatectomy, laparoscopic cholecystectomy or laparoscopic devascularization must be performed together. As a result, it will be possible to expand the indication of ELAT safely and radically.     

Efficacy and safety of novel oral fluoropyrimidine anticancer drug, TS-1 for advanced and recurrent gastric cancer patients

The efficacy and safety of the oral fluoropyrimidine TS-1, which contains a dihydropyrimidine dehydrogenase (DPD) inhibitor, were examined in fifty-five patients with gastric cancer. The patients were divided into 28 with measurable cancer lesions (TUM group) and 27 without them (ADJ group). The total number of courses was 164 (mean: 5.9 courses) in the TUM group and 146 (mean; 5.4 courses) in the ADJ group. The response rate in the TUM group, excluding three patients who could not be evaluated because of incomplete administration, was 40% (CR: 4, PR: 6, NC: 6, PD: 9). Among responders, the mean number of courses to response was 2.2 and the median survival time (MST) was 21.7 months. In terms of safety, adverse reactions appeared in forty-five patients (82%) and the incidence was higher in the ADJ group. Major toxicities were leukopenia (38%), anorexia (27%), increased total bilirubin concentration (25%) and diarrhea (24%). Adverse reaction of grade 3 was found in only three patients (5.5%) and there were no drug-related deaths. In conclusion, TS-1 is safe and effective if attention is given to biweekly examinations for the development of adverse reactions.     

TS-1 and lentinan combination immunochemotherapy for advanced or recurrent gastric cancer: a preliminary report

The immunocompetence and nutritional state of patients with advanced or recurrent gastric cancer is low, making it important to conduct chemotherapy while at the same time improving or maintaining their immunocompetence and nutritional state. To reduce the side effects but not the antitumor effect of TS-1, a 2-week regime of TS-1, and 1-week drug-free interval, in combination with the immunotherapeutic agent lentinan (LNT) was started in 5 patients with advanced or recurrent gastric cancer. Toxicity, efficacy, immunocompetence and nutritional state were investigated preliminarily to examine whether or not usefulness of lentinan could be evaluated. The IAP tended to decrease. TS-1 and lentinan combination immunochemotherapy was able to be carried out safely in patients with advanced recurrent gastric cancer. In order to examine the usefulness of combined LNT, it is thought to be necessary to perform a randomized trial using toxicity and not only efficacy but QOL and immunological and nutritional parameters as indicators.     

Advances in brachytherapy--focusing on the permanent implant for early prostate carcinoma

Even in the modern era of advanced external radiotherapy, brachytherapy is an important and useful modality of radiotherapy. In North America and Europe, it has been noted that the proportion of prostate cancer patients treated by HDR or LDR interstitial brachytherapy is rapidly increasing, as it offers several practical and theoretical advantages over external radiotherapy. HDR treatment with 192Ir remote afterloader provides an optimized dose distribution controlled by an accurate dwell time and position of 192Ir source. LDR brachytherapy is a simple, minimally invasive, and outpatient based procedure that avoids hospitalization and allows the patient an early recovery and rapid return to normal activities. It has produced good 10-year outcome with relatively low morbidity. Although in Japan this treatment was behind North America and Europe, the 125I-seed source was approved by the Japanese FDA and a rule for patient discharge was developed recently. The first case was treated in September 2003 and this treatment is expected to become an important option for early prostate cancer. Several areas of brachytherapy including treatment planning, choice of radionuclide, treatment procedure, and treatment outcome are discussed in this paper.     

Clinical evaluation of the effect of daio (rhei rhizoma) on the progression of diabetic nephropathy with overt proteinuria

We studied the effect of traditional herbal medicines containing daio (Rhei Rhizoma) on the long-term progression of diabetic nephropathy with overt proteinuria in eight patients [mean age 60 (45-73) years; duration of diabetes 18 (7-36) years]. At the beginning of the study, mean HbA1c was 8.2% and mean serum creatinine was 1.0 +/- 0.3 mg/dl. Everypatient had diabetic neuropathy and retinopathy. Three of the patients had hypertension and four had ischemic heart disease. After 107 +/- 25 months, the mean serum creatinine level had significantly increased to 4.8 +/- 2.6 mg/dl. The mean serum creatinine levels of five patients not advancing to dialysis treatment increased from 1.2 +/- 0.3 to 3.2 +/- 1.0 mg/dl, and the three patients requiring dialysis increased from 0.8 +/- 0.1 to 7.5 +/- 2.1 mg/dl. In the control group, treated without traditional herbal medicines, the mean serum creatinine level had significantly increased from 1.0 +/- 0.3 to 9.5 +/- 1.9 mg/dl after 71 +/- 12 months. All of the control group required dialysis treatment. Diabetic nephropathy with overt proteinuria is reported to develop into renal failure after 6-7 years. In this retrospective study, traditional herbal medicines with Daio were considered to be effective in prolonging the pre-dialysis period of diabetic nephropathy.     

Identification of benzo(a)pyrene diol epoxide-binding DNA fragments using DNA immunoprecipitation technique

Benzo(a)pyrene diol epoxide (BPDE), an active metabolite of the tobacco carcinogen benzo(a)pyrene, can induce p53 gene mutation, down-regulate retinoic acid receptor beta, and increase cyclooxygenase-2 expression in human epithelial cells. However, it remains unknown whether these effects are direct or indirect. To investigate the direct effects of BPDE on gene expression, we used our newly developed DNA immunoprecipitation technique to identify and clone BPDE-binding DNA fragments. A total of 67 fragments were sequenced and grouped into four categories after their sequences were blasted in the GenBank database: (a). 15 fragments matched known gene sequences; (b). 24 matched expressed sequence tag clones; (c). 22 matched genomic DNA of unknown genes; and (d). 6 clones did not show any homology with GenBank sequences known to date. The 67 fragments include DNA repair and apoptosis-related genes, zinc finger protein, cellular enzymes, expressed sequence tag clones, and CpG islands. These data further demonstrate that BPDE-induced gene alterations are important events in carcinogenesis and that the identification of the resulting clones may help us to better understand the mechanisms of BPDE-induced carcinogenesis.     

Methylation of the thyroid-stimulating hormone receptor gene in epithelial thyroid tumors: a marker of malignancy and a cause of gene silencing

Thyroid-stimulating hormone receptor (TSHR) expression is frequently silenced in epithelial thyroid cancers associated with decreased or absent TSH-promoted iodine uptake. To study the underlying molecular mechanism of decreased TSHR expression, we examined the methylation status of the TSHR gene promoter by sequencing bisulfite-treated DNA from thyroid tumors. After identification of methylated sites by sequencing bisulfite-treated DNA, we used methylation-specific polymerase chain reaction and found frequent CpG methylation in papillary thyroid cancer (23 of 39 patients; 59%) and follicular thyroid cancers (7 of 15 patients; 47%). In contrast, we saw no methylation in normal thyroid tissues and benign adenomas (0 of 8 patients; 0%). In human thyroid tumor cell lines, we observed that TSHR was normally expressed at the protein and mRNA level in cells where the TSHR gene was unmethylated, whereas it was silenced in cell lines where the TSHR promoter was hypermethylated. Treatment of the latter cells with a demethylating agent partially restored TSHR expression. We thus demonstrate aberrant methylation of human TSHR as a likely molecular pathway responsible for the silencing of this gene in thyroid cancers. We propose that methylation of TSHR may provide a novel diagnostic marker of malignancy and a basis for potential use of demethylating agents in conjunction with TSH-promoted radioiodine therapy for epithelial thyroid cancers.     

Antitumor effect by interleukin-11 receptor alpha-locus chemokine/CCL27, introduced into tumor cells through a recombinant adenovirus vector

In this study, we examined antitumor activity of a mouse CC chemokine ILC/CCL27 and a mouse CX(3)C chemokine fractalkine/CX(3)CL1 in vivo. We generated recombinant adenovirus vectors with a fiber mutation, encoding mILC (Ad-RGD-mILC) and mFKN (Ad-RGD-mFKN). We confirmed tumor cells infected with Ad-RGD-mILC and Ad-RGD-mFKN to express and release these chemokines. Tumor rejection experiments in vivo were carried out by inoculating OV-HM cells infected with Ad-RGD-mILC or Ad-RGD-mFKN into immunocompetent mice. mILC significantly suppressed the tumor growth, whereas no such significant effect was observed by mFKN. The antitumor activity induced by mILC was T cell dependent, involving both CD4(+) and CD8(+) T cells. Immunohistochemical analysis revealed accumulation of both CD3(+) lymphocytes and NK cells in the tumor tissue transduced with mILC and mFKN. However, there was a significant difference in the distribution of infiltrating cells. Furthermore, mFKN appeared to have an angiogenic activity, which might have masked its tumor suppressive activity. Collectively, ILC/CCL27 may be a good candidate molecule for cancer gene therapy.