Oleamide is a selective endogenous agonist of rat and human CB1 cannabinoid receptors.

1. The ability of the endogenous fatty acid amide, cis-oleamide (ODA), to bind to and activate cannabinoid CB(1) and CB(2) receptors was investigated. 2. ODA competitively inhibited binding of the nonselective cannabinoid agonist [(3)H]CP55,940 and the selective CB(1) antagonist [(3)H]SR141716A to rat whole-brain membranes with K(i) values of 1.14 microm (0.52-2.53 microm, Hill slope=0.80, n=6) and 2.63 microm (0.62-11.20 microm, Hill slope=0.92, n=4), respectively. AEA inhibited [(3)H]CP55,940 binding in rat whole-brain membranes with a K(i) of 428 nm (346-510 nm, Hill slope=-1.33, n=3). 3. ODA competitively inhibited [(3)H]CP55,940 binding in human CB(1) (hCB(1)) cell membranes with a K(i) value of 8.13 microm (4.97-13.32 microm, n=2). In human CB(2) transfected (hCB(2)) HEK-293T cell membranes, 100 microm ODA produced only a partial (42.5+/-7%) inhibition of [(3)H]CP55,940 binding. 4. ODA stimulated [(35)S]GTPgammaS binding in a concentration-dependent manner (EC(50)=1.64 microm (0.29-9.32 microm), R(2)=0.99, n=4-9), with maximal stimulation of 188+/-9% of basal at 100 microm. AEA stimulated [(35)S]GTPgammaS binding with an EC(50) of 10.43 microm (4.45-24.42 microm, R(2)=1.00, n=3, 195+/-4% of basal at 300 microm). Trans-oleamide (trans-ODA) failed to significantly stimulate [(35)S]GTPgammaS binding at concentrations up to 100 microm. 5. ODA (10 microm)-stimulated [(35)S]GTPgammaS binding was reversed by the selective CB(1) antagonist SR141716A (IC(50)=2.11 nm (0.32-13.77 nm), R(2)=1.00, n=6). 6. The anatomical distribution of ODA-stimulated [(35)S]GTPgammaS binding in rat brain sections was indistinguishable from that of HU210. Increases of similar magnitude were observed due to both agonists in the striatum, cortex, hippocampus and cerebellum. 7. ODA (10 microm) significantly inhibited forskolin-stimulated cyclic AMP (cAMP) accumulation in mouse neuroblastoma N1E 115 cells (P=0.02, n=11). ODA-mediated inhibition was completely reversed by 1 microm SR141716A (P<0.001, n=11) and was also reversed by pretreatment with 300 ng ml(-1) pertussis toxin (P<0.001, n=6). 8. These data demonstrate that ODA is a full cannabinoid CB(1) receptor agonist. Therefore, in addition to allosteric modulation of other receptors and possible entourage effects due to fatty acid amide hydrolase inhibition, the effects of ODA may be mediated directly via the CB(1) receptor.

Salvage chemotherapy with paclitaxel in platinum-resistant advanced ovarian cancer patients.

Encouraging results with Paclitaxel are reported in ovarian cancer patients relapsing and progressing after platinum-based chemotherapy; however, the two populations have different probabilities of a response to a second-line treatment. Here we report the results achieved in 39 patients with platinum-refractory ovarian cancer, treated with Paclitaxel 175 mg/qm2 (or 135 mg/m2 if heavily pretreated) using 3-hour intravenous infusion every 3 weeks, in an attempt to verify the activity of this drug in platinum-resistant patients. The toxicity was mild to moderate and primarily hematologic and neurologic. The objective response rate is 12.8% with no complete responses. The response duration was brief and the median survival 6 (range 1-17) months. An accurate cost-benefit balance is necessary before routinely use of Paclitaxel in platinum-refractory patients. Further research is needed to determine the optimal role of Paclitaxel in the whole therapeutic strategy for ovarian cancer.

Cisplatin-associated anaemia in patients with solid tumours. A retrospective evaluation and considerations relative to erythropoietin administration.

We have reviewed the incidence of cisplatin-induced anaemia in patients affected with solid tumours treated with at least three courses of first-line cisplatin-containing regimens. In our experience, a low percentage (5%) of patients required transfusions of red blood cells. We think it is of the utmost importance to adopt uniform criteria in monitoring and treatment of patients at risk of developing cisplatin anaemia and to identify subsets of patients to eventually treat with erythropoietin.

Cisplatinum based chemotherapy: role of the antiserotoninergic ondansetron in prevention of emesis.

Serotonin is a neurotransmitter involved in chemotherapy-induced emesis and ondansetron is a new drug endowed with selective antagonism against the 5HT3 receptors. Phase I-II studies have demonstrated its activity against acute emesis after single-dose cisplatin, reporting particularly low toxicity; in comparative studies with high-dose metoclopramide, it has been proved to be more effective and completely devoid of extrapyramidal side effects. Ondansetron has shown its activity and safety also in multiple-day cisplatin regimens. Its antiemetic efficacy is improved by the addition of dexamethasone. Preliminary data suggest its role also when used in single-dose administration. Its activity in the delayed phase of cisplatin emesis needs to be further explored.

A cisplatinum-cyclophosphamide regimen in advanced ovarian cancer: reporting 5-year results.

The following paper reports the evaluation of 53 consecutive patients with advanced ovarian epithelial carcinoma (FIGO stage III-IV), treated between October 1984 and December 1987 with immediate or delayed cytoreduction surgery and chemotherapy. Combination chemotherapy consisted of cisplatinum 45 mg/m2 i.v. for 2 consecutive days and cyclophosphamide 900 mg/m2 i.v. on the second day, administered every 28 days for a maximum of 8 courses. Objective responses were observed in 35 of 50 evaluable patients (70%), 17 (34%) of whom were pathological complete remissions (pCR). For patients with minimal residual disease before chemotherapy a higher pCR rate was achieved (10/20 vs. 7/30; p = N.S.). Median survival time of all patients was 29 months; subjects with minimal residual disease and good performance status before treatment had higher survival (48 vs. 22 months-p < 0.05 and 29 vs. 9 months-p < 0.05, respectively). Median time to progression was 25 months. After a median follow-up of 60 months, 15 (28%) patients were alive, 14 of whom disease-free. Toxicity was moderate with a particularly low incidence of nephrotoxicity and no case of serious long-lasting neuropathy. These findings suggest that the described combination has an efficacy comparable to other CDDP-containing combinations, using 2, 3 or more drugs, with a low incidence of acute serious toxicities and of disabling delayed sequelae.

A phase II study of combination chemotherapy in advanced ovarian carcinoma with cisplatin and cyclophosphamide plus reduced glutathione as potential protective agent against cisplatin toxicity.

AIMS AND BACKGROUND: The clinical use of cisplatin (CDDP), one of the most active agents in advanced ovarian cancer, is limited by nephrotoxicity and cumulative neurotoxicity. In preclinical studies, reduced glutathione (GSH) demonstrated a protective action against CDDP nephrotoxicity. We treated 20 patients with advanced ovarian carcinoma, with polychemotherapy containing CDDP + GSH, to assess the protective action of GSH against CDDP nephrotoxicity. METHODS: Between January 1988 and December 1989, 20 patients, with advanced ovarian carcinoma (St. III-IV-FIGO), not pretreated received CDDP: 45 mg/m2 i.v., on day 1-2, + cyclophosphamide (CPA): 900 mg/m2 i.v. on day 2 + GSH 2500 mg i.v. in normal saline 100 ml (in 15 min), before CDDP, every 21-28 days. RESULTS: A pathologic complete response rate (PCR) of 55% (11/20) was observed (7/14 patients with bulky disease). Median survival was 26.5 months and 5 patients were still alive and disease free at 35 months. Toxicity was limited, without any case of nephrotoxicity. CONCLUSIONS: On the basis of our previous experience with the same regimen without GSH, this study suggests that also in the clinical setting, GSH has no negative interference on CDDP activity and that GSH might improve the therapeutic index of CDDP. However, our data need to be confirmed by large randomized clinical studies.

[The value of xeroradiographic patterns in the diagnosis of breast diseases (author's transl)]. / Il valore diagnostico della semeiotica xeroradiografica nello studio delle affezioni mammarie.

The purpose of this study was to establish the value of xeroradiographic patterns and their applicability in the automatic diagnosis of breast diseases. Such an evaluation is based on the comparison with the histologic examination, irrespective of the overall diagnostic judgement previously formulated. From an analysis of the material examined it was possible to ascertain the distribution frequency, the sensitivity, the specificity, the discriminating capacity, and finally the weight of each radiologic sign considered. There are xeroradiographic signs that are apparent almost exclusively in the malignant pathology and therefore can be considered as positive indices of the malignancy of the alteration. The specificity of the radiologic signs considered is very high, whereas the same cannot be said for the sensitivity. Moreover, a linear discriminating analysis made it possible to identify those semiologic elements which, with a minor probability of error, would attribute the pathologic process to the class verified histologically, for malignant neoplasms as well as benign tumors and dysplastic processes.

Diagnostic accuracy of xeromammography.

The analytical study of the case material has allowed a precise evaluation of the distribution by age groups of the different pathologic processes of the breast, of the localization and dimensions of malignant tumors, as well as the diagnostic accuracy for those cases histologically ascertained and those with a follow-up. The diagnostic accuracy and the consequent reliability of the xeroradiographic method for the diagnosis of breast cancer is distinctly superior to that reported in the literature for traditional mammography, whereas for the differential diagnosis between circumscribed dysplastic manifestations and benign tumors xeromammography is not sufficiently reliable. The authors critically discuss the results and in particular the problem of false positives, which also include diagnostic errors that cannot be avoided in that they directly derive from the pathologic morphology of the disease process (plasma cell mastitis and sclerosing adenosis). As regards the problem of false negatives, they can be reduced within certain limits by resorting to other instrumental investigations. However, there are cases (1% of the malignant neoplasias histologically ascertained) that present a completely negative xeroradiographic finding. There are the limits of the radiologic investigation which cannot in any way be surmounted.