Mechanism for bone invasion of oral cancer cells mediated by interleukin-6 in vitro and in vivo

BACKGROUND: Osteoclastic bone resorption is an important step in bone invasion in several malignancies. Although interleukin (IL)-6 accelerates osteoclastic bone resorption, it remains unclear whether IL-6 may be involved in bone invasion of oral cancer. METHODS: The pit formation assay with calf femur-derived bone slices was performed to examine the bone-resorbing activity of osteoclasts and cancer cells. The chemotaxis activity of the culture media was analyzed by the use of Boyden chamber technique. Nude mice, which were inoculated with IL-6-producing oral cancer cells into masseter, were treated with anti-IL-6 neutralizing antibody, and mandibular-bone invasion of the cells was assessed. RESULTS: BHY, a bone-invasive oral cancer cell line, but not HNT, a noninvasive cell line, produced large amounts of IL-6. In a pit formation assay, addition of conditioned medium (CM) derived from BHY but not HNT increased osteoclastic bone resorption, and the effects were inhibited by anti-IL-6 antibody. BHY-secreted IL-6 showed significant chemotaxis activity for osteoclasts. Of note, CM from the cocultivation of osteoclasts and BHY markedly enhanced the cancer cell migration, and the chemotaxis activity was significantly reduced when anti-IL-6 antibody was added into the coculture and then CM were collected, but not when the antibody was added into the CM after they were collected. Furthermore, treatment with anti-IL-6 antibody almost completely inhibited mandibular bone invasion of BHY in nude mice. CONCLUSIONS: These results strongly suggest that IL-6 secreted by oral cancer cells plays a significant role in bone invasion.     

Prediction of hepatic first-pass metabolism and plasma levels following intravenous and oral administration of barbiturates in the rabbit based on quantitative structure-pharmacokinetic relationships

Based on the concept of physiological pharmacokinetics, the hepatic first-pass metabolism and plasma levels following intravenous and oral administration of barbiturates in the rabbit was predicted based on the relationships between principle kinetic parameters and lipophilicity (chloroform-water partition coefficient). Good log-log linear relationships between kinetic parameters and lipophilicity were obtained for the seven barbiturates examined. The values of correlation coefficient were improved slightly by using the corrected values for partition coefficients of nonionic molecules in the cases of principle parameters such as drug-protein and drug-blood cell affinity, intrinsic hepatic clearance, and unbound volume of distribution. There was also a good linear relationship between absorption rate constant (mean absorption time) and lipophilicity. The mean hepatic transit time was negligible for the most lipophilic drug (hexobarbital) examined; this suggests that the mean absorption time for these barbiturates does reflect the absorption process. The available fraction in relation to hepatic first-pass metabolism was well predicted from the lipophilicity by both well-stirred and parallel-tube models, and the difference in the values predicted by both models was minimal. There were good relationships between predicted and observed values for plasma levels after intravenous and oral administration, except for two (cyclobarbital and phenobarbital) of the seven drugs used. The great difference between predicted and observed values for these two drugs was considered due to substituent effects in liver metabolism.     

Evidence-based guidelines for treatment of uterine body neoplasm in Japan: Japan Society of Gynecologic Oncology (JSGO) 2009 edition

Endometrial carcinoma is one of the most common gynecologic malignancies in Japan and its incidence has increased recently. Although surgery is the cornerstone of the management of patients with endometrial cancer, there is significant variation in Japan with regard to the type of hysterectomy employed. Additionally, it remains controversial whether full nodal staging is required in all patients. Furthermore, adjuvant therapy differs between Japan and Western countries. To delineate clearly the standard of care for endometrial cancer treatment in Japan, the guidelines for the treatment of endometrial cancer were published in 2006 and revised in 2009. The 2009 edition included topics not addressed in the previous edition including the treatment of mesenchymal tumors, for example leiomyosarcoma, and sections covering the treatment of serous and clear-cell adenocarcinoma. These guidelines are composed of nine chapters and include nine algorithms. The guidelines also contain fifty-one clinical questions (CQs) and each CQ consists of recommendations, background, explanations, and references. The treatment recommendations herein are tailored to reflect current Japanese clinical practice and ensure equitable care for all Japanese women diagnosed with endometrial cancer.     

The efficacy of aprepitant and palonosetron on cisplatin doublet in lung cancer

Nausea and vomiting are major adverse reactions in cancer chemotherapy, and affect quality of life (QOL). We performed a retrospective study that examined the efficacy of aprepitant and palonosetron for chemotherapy-induced nausea and vomiting (CINV) on patients taking cisplatin doublets for lung cancer. The study subjects were 73 patients. A 5-HT(3) group received old-generation 5-HT(3) receptor antagonists and dexamethasone for preventive treatment (32 patients). An A group received old-generation 5-HT(3) receptor antagonists, aprepitant and dexamethasone (22 patients). An A+P group received palonosetron, aprepitant and dexamethasone (19 patients). On acute emesis (occurring within 24 hours after chemotherapy), there was no significant difference in the complete suppression rate of nausea and vomiting among the three groups. However, on delayed onset emesis (occurring between 24 to 120 hours), the complete suppression rate of nausea was significantly higher in the A+P group (57. 9%) than in the 5- HT(3) group (16. 7%) and A group (23. 8%). Significantly better efficacy was seen in the 5-HT(3) group and A group in the complete suppression rate of vomiting, and in the need of rescue medication rates on delayed-onset emesis. The cost of antiemesis was 19, 735 yen for the 5-HT(3) group, 32, 252 yen for the A group and 15, 557 yen for the A+P group. In conclusion, it was suggested that concurrent administration of palonosetron, aprepitant and dexamethasone for CINV on cisplatin doublet in lung cancer is a clinically useful treatment that might reduce the economic burden on patients.     

Regional Differences in Calcium Sensitivity in the Guinea-pig Intestine

The effect of the Ca²⁺-channel antagonist nicardipine on the basal tone of six segments (duodenum, jejunum, ileum, proximal colon, distal colon and rectum) of the guinea-pig intestine has been investigated in muscle preparations. Nicardipine reduced the basal tone of the proximal and distal colon but not of the duodenum, jejunum, ileum and rectum. Similarly, when each segment was incubated in Ca²⁺-free medium, the basal tone of the proximal and distal colon, but not that of the other four segments, was reduced. The reduced basal tone recovered after cumulative addition of Ca²⁺ in both colon preparations. The basal tone of the distal colon was partly reduced by tetrodotoxin, atropine and clonidine. Conversely, l -typeCa²⁺-channel antagonists (Cd²⁺, verapamil and nicardipine), but not the T-type Ca²⁺-channel antagonist Ni²⁺, completely reduced the basal tone of the distal colon. These results indicate that in the regulation of basal tone there are additional regional differences in the effect of Ca²⁺ influx into the cells from the extracellular fluid which might involve l -type-like Ca²⁺ channels and might partly be because of neuronal factors.     

Pharmacokinetic Analysis of Increased Toxicity of 2-sec-Butylphenyl Methylcarbamate (BPMC) by Fenitrothion Pretreatment in Mice

Pharmacokinetk Analysis of Increased Toxicity of 2-sec-ButylphenylMethylcarbamate (BPMC) by Fenitrothion Pretreatment in Mice.TSUDA, S., MIYAOKA, T., IWASAKI, M., AND SHIRASU, Y. (1984).Fundam. Appl. Toxicol. 4, 724–730. The potentiating effectof O,O-dimethyl O-(3-methyl-4-nitrophenyl) phosphorothioate(fenitrothion) on the toxicity of 2-sec-butylphenyl methylcarbamate(BPMC) in male mice was analyzed pharmacokinetically. The animalspretreated by dietary administration of 1000 ppm fenitrothionfor 1 week (4.4% of the po LD50 daily) did not show toxic symptomsexcept for a slight decrease in body weight In the fenitrothion-pretreatedmice, toxicity of fenitrothion was not changed but a fivefoldpotentiation was observed in po and ip acute lethality and athreefold potentiation of iv lethality of BPMC. Toxic signsafter BPMC administration were similar regardless of fenitrothionpretreatment or of route of administration. Fenitrothion pretreatmentfollowed by BPMC administration (20 mg/kg po or 8 mg/kg iv,approximate LD5 in the pretreated mice) significantly increasedthe plasma BPMC concentration and the total area under the plasmaconcentration versus time curve (AUG_0-. The pretreatment increasedthe oral AUC_0-, more greatly than the iv AUC_0-, (for po, 6.3-fold;for iv, 2.0-fold). The oral systemic availability of BPMC (fractionreaching systemic circulation) was increased by fenitrothiontreatment to 3.3-fold. These results suggest that a major causeof the potentiation may be the increase in amount of BPMC inthe systemic circulation.     

Successful Radiofrequency Current Catheter Ablation of Sustained Ventricular Tachycardia

We performed radiofrequency current catheter ablation in two patients with nonischemic sustained ventricular tachycardia (VT). In one patient, two morphologically distinct VTs were induced by electrical stimulation. One showed right bundle branch block pattern and the other left bundle branch block pattern. The earliest site of activation during each VT was determined at the septum of the right ventricle. However, these two sites were close to the His-bundle elecfrogram recording area. In the other patient, a VT with a left bundle branch block pattern occurred spontaneously after the administration of isoproterenol. The earliest site of activation during VT was determined at the outflow tract of the right ventricle. During tachycardia, radiofrequency current ablation (40 W ± 30 sec) was delivered to the earliest site of activation, A few seconds after fulguration, each VT was terminated and additional radio-frequency currents were given near these sites. After the ablation, VT could not be induced by the electrical stimulations, nor did it recur. No side effects were observed and the atrioventricular conduction remained intact. We feel that nonischemic VTs could possibly be treated by using radiofrequency current catheter ablation.     

Effects of transforming growth factor-β1 on formation and activation of osteoclasts

Transforming growth factor-₁ (TGF-₁) has biological functions in various types of cells. However, its roles in the regulation of osteoclast formation and function are unclear. To examine them, we employed a culture system in which unfractionated cells obtained from long bones of 13-day-old mice were cultured on a dentine slice. We found that TGF-₁ has a potent inhibitory effect on osteoclastic bone resorption at a dose of 0.2–5 ng/ml. By electron microscopy the osteoclasts appeared to have fewer mitochondria and ruffled borders than those in control cultures. But in the presence of 1,25-dihydroxyvitamin D₃, [1,25-(OH)₂D₃], TGF-₁ at a dose of 0.2–1 ng/ml stimulated the formation of osteoclasts from unfractionated bone cell cultures in which preexistent osteoclasts had degenerated. Thus, using stromal cell-free he-mopoietic blast cells, we examined the direct action of TGF-₁ on osteoclast precursors. Although TGF-₁ inhibited tartrate-resistant acid phosphatase-positive (TRAP) multinucleate cell (MNC) formation induced by 1,25-(OH)₂D₃, the conditioned medium (CM) of TGF-₁-treated MC3T3-E1 cells stimulated such formation. These results suggest that TGF-₁ inhibits osteoclastic bone resorption but stimulates osteoclast formation via the action of factor(s) produced by TGF-₁-treated osteoblasts in the presence of 1,25-(OH)₂D₃.     

Hormonal environment following treatment with a small dose of estrogen--small dose of estrogen alone and in combination with an anti-androgen

The testosterone, luteinizing hormone (LH), follicle stimulating hormone (FSH) and prolactin levels were measured by radioimmunoassay up to one year in 21 patients with prostatic carcinoma treated with diethylstilbestrol diphosphate (DESP), 50 mg/day, and chlormadinone acetate (CMA), 100 mg/day. The purpose of this treatment was to reduce the cardiovascular side effects which were believed to occur dose-dependently and to achieve the direct drug action to the prostate gland. The same measurements were made on 9 patients treated with DESP, 50 mg/day, alone. Marked reduction of plasma testosterone and FSH levels with weaker LH suppressions was observed during the first 1-3 months in both groups. The same levels were maintained up to the end of follow-up in DESP and CMA treatment group. In the DESP treatment group, the plasma level of testosterone showed a gradual increase to 1.0 +/- 0.5 ng/ml at the sixth month. Prolactin level increased gradually in both groups. Cardiovascular side-effects were found in 29% of the patients treated with DESP and CMA and in 22% of those treated with DESP alone. In two patients in the former group gynecomastia with lactation was observed.