Inositol 1,4,5-trisphosphate turnover enzymes--activities and subcellular distribution in hepatocarcinogenesis

The metabolism of inositol 1,4,5-trisphosphate and inositol 1,3,4,5- tetrakisphosphate in homogenates and sub-fractions from normal rat liver and premalignant liver nodules was investigated. The activities of 5-phosphatase, expressed as pmol converted substrate per minute and mg protein, were equal when using the two substrates, and did not differ between normal and nodular homogenates. Subcellular fractions were purified by sequential steps of differential centrifugation and density gradient fractionation procedures. The total phosphatase activity was found to be distributed between cytosol (15%) and membraneous fractions (75%), with most of the enzyme activity residing in the plasma membranes. A doubling of phosphatase specific activity was seen in the nodular low density membrane fraction, containing Golgi apparatus and endosomes, as compared with normal liver. Inositol 1,4,5- trisphosphate 3-kinase activity was found to be exclusively cytosolic. No difference in this enzyme was seen between the two tissue types studied. Vasopressin (0.2 or 2 microM) had no effect either on phosphatase or kinase activity. The compartmentalization of inositol polyphosphate 5-phosphatase activity presents a possible explanation of earlier findings that premalignant liver tissue was able to respond with inositol 1,4,5-trisphosphate, but not inositol 1,3,4,5- tetrakisphosphate formation after agonist stimulation.      

Weekly chemotherapy in advanced prostatic cancer.

This randomised phase II study was performed in order to evaluate the effectiveness of a weekly chemotherapy regimen in advanced prostatic carcinoma patients (stage D2) refractory to hormonal therapy. Seventy-two cases were studied: they were randomised in a 2:1 ratio to receive either epirubicin (30 mg m-2 weekly) or doxorubicin (25 mg m-2 weekly); 48 patients received epirubicin and 24 received doxorubicin. After 12 courses of chemotherapy, the 45 evaluable patients in the epirubicin arm showed a response rate of 37.7% and the 21 evaluable patients in the doxorubicin arm showed a response rate of 33.3% (P = 0.51). Pain intensity, bone and prostatic tumour markers rapidly and significantly decreased in responders. An improvement in physical symptoms, functional conditions and in emotional well-being was observed in the majority of the treated patients. The histological analysis of bone metastases, performed before and after 12 courses of chemotherapy showed a significant reduction in neoplastic invasion and in new bone formation in responders. Cardiac performance worsened in five out of 45 patients and in ten out of 21 during the first 12 courses of epirubicin or doxorubicin respectively (P = 0.014). The median survival was 12.5 months in the epirubicin arm and 8.0 months in the doxorubicin arm (P = 0.042). Our data indicate that in advanced prostatic carcinoma, a weekly epirubicin regimen may give rapid palliative results, similar to that of doxorubicin, but with less side-effects.     

A BPA survey of recently appointed consultants

A postal survey of recently appointed consultant paediatricians was undertaken to determine whether they perceived their training had adequately equipped them for their current job. The response rate was 69% (207/299). After excluding replies from consultants trained outside the UK the analysis was carried out on 167 replies. Trainees held a mean 5.2 posts during general and higher professional training, necessitating a mean 1.8 house moves. Altogether 82% felt moves were beneficial to training but 46% found moves 'very disruptive' to family life. Only 12% of district general hospital and 22% of teaching hospital senior registrars took two research sessions a week. Supervision and training in research was absent or poor for more than 60%; 24% felt major changes and 55% moderate changes were needed to current training. Training in non-clinical skills was particularly in demand and a curriculum for both trainers and trainees with regular appraisals is required. Research at senior registrar level needs review and educational methods improved to achieve better training in a shorter period.     

Flavonol glycosides from Aristeguietia discolor reduce morphine withdrawal in vitro

The effects of extracts, partially purified fractions and four flavonol glycosides 1-4 from Aristeguietia discolor were investigated on the naloxone-precipitated withdrawal contraction of the acute morphine dependent guinea-pig ileum in vitro. After a 4 min in vitro exposure to morphine a strong contraction of guinea-pig isolated ileum was observed after the addition of naloxone. Both MeOH extract (50, 100 and 200 mg/mL), the partially purified fractions I, L, M and N (50, 100 and 200 mg/mL) and flavonol glycosides 1-4 (1 x 10(-4) 5 x 10(-5) 1 x 10(-5) M), injected 10 min before morphine, were capable of blocking the naloxone-induced contraction after exposure to morphine in a concentration-dependent fashion. The results of the present paper suggest that flavonol glycosides from Aristeguietia discolor may play an important role in the control of morphine withdrawal.     

Feasibility of oral ciprofloxacin for the outpatient management of febrile neutropenia in selected children with cancer

BACKGROUND: Children with cancer who develop an episode of chemotherapy-induced febrile neutropenia usually are admitted to the hospital for intravenous empiric antibiotic therapy. In the current study, the authors examined the use of ciprofloxacin as outpatient management in selected patients with fever during an episode of neutropenia. METHODS: Febrile neutropenic patients with a diagnosis of cancer were eligible for outpatient management with oral ciprofloxacin if they appeared well and demonstrated the following characteristics: age 1-21 years, malignancy in remission, absolute phagocyte count > 100/mm(3), > 7 days since the initiation of the last course of chemotherapy, and reliable parents. Eligible children received a single dose of ceftazidime and were observed for 2-23 hours. Patients were discharged receiving oral ciprofloxacin (20/mg/kg/day divided in 2 doses) until the patient was afebrile for 24 hours, had sterile blood cultures, and had evidence of bone marrow recovery. Patients were admitted if they appeared toxic, had positive blood cultures, or were febrile for >/= 5 days. RESULTS: Forty-five evaluable episodes occurred in 32 children. Forty of the 45 patients (89%) were treated successfully in the outpatient setting. The 95% lower confidence bound on the proportion of successful outcomes was 70%. Five children required hospitalization: 2 due to noncompliance, 1 to receive intravenous acyclovir for herpes zoster, and 2 (4%) whose blood cultures were positive for Streptococcus viridans and S. pneumoniae. All had uncomplicated hospitalizations. CONCLUSIONS: The current study demonstrates that very carefully selected, low risk patients with febrile neutropenia may be treated successfully without hospitalization using oral ciprofloxacin. Additional research is required to refine further the optimal criteria for the selection of appropriate patients for outpatient management.     

Drug-induced modulation of carcinoembryonic antigen (CEA) expression in neoplastic cells from a patient with rectal cancer

Treatment with 5-fluorouracil (5-FU) or recombinant interferon-gamma (IFN), alone or in combination, was found to increase carcinoembryonic antigen (CEA) expression in several carcinoma cell lines. In this study we examined the in vitro effect of these agents on CEA expression of tumor cells, obtained from a patient operated for rectal cancer. The results showed that exposure of cancer cells to 5-FU or to IFN resulted in increased CEA levels in terms of percentage of CEA-positive cells and mean fluorescence values, as indicated by FACS analysis. However, drug combination did not induce CEA expression higher than that provided by single agents alone. Treatment with 5-FU or with IFN produced a reduction of the total number of viable cells. Moreover, Western blot analysis revealed that exposure of cancer cells to each drug was followed by a substantial increase of the total cellular CEA content. On the contrary, 5-FU in combination with IFN did not increase the expression of the antigen more than that obtained by single agents. Noteworthy, exposure of CEA-negative cells from adjacent normal rectal tissue to both agents alone or in combination, did not result in CEA induction. In conclusion, the present results suggest new approaches aimed at (a) increasing the sensitivity of diagnostic procedures based on detection of CEA-positive tumor cells; (b) facilitating the recognition of CEA-positive cancer cells by immune responses induced by anti-CEA peptide vaccines.     

Antibody as carrier of 131I in cancer diagnosis and treatment.

Cell-surface localizing heterologous antibodies against mouse EL4 lymphoma, Ehrlich ascites carcinoma, and several human malignant tumors could be bound to varying amounts of 131I without interfering with the reactivity of these antibodies with their respective tumor cells. Exposure of the mouse tumor cells to radio-iodinated antitumor antibodies in vitro, or the injection of radio-iodinated antitumor antibodies into mice preinoculated with tumor cells resulted in either partial or complete tumor inhibition depending upon the amount of 131I activity carried by the antibodies. Injection of comparable amounts of the immunoglobulin alone or of 131I bound to normal globulin did not cause any tumor inhibition. Intraperitoneally injected radio-iodinated anti-EL4 antibody was found to localize preferentially in the subcutaneous transplants of EL4 lymphoma. Similar localization of intravenously injected radio-iodinated antibodies was observed in the metastases of two cancer patients.