Effects of a combination of 3,4-methylenedioxymeth amphetamine and caffeine on real time stimulated dopamine release in the rat striatum: Studies using fast cyclic voltammetry.

It is well documented that caffeine exacerbates the hyperthermia associated with acute exposure to 3,4-methylenedioxymethamphetamine (MDMA) in rats. Previous reports have also indicated that MDMA-related enhancement of dopamine release is exacerbated in the presence of caffeine. In the present study we have examined whether the effects of MDMA on real-time stimulated dopamine release, in the absence of uptake inhibition, are accentuated in the presence of caffeine. Isolated striatal slices from adult male Wistar rats were treated acutely with MDMA, caffeine, or a combination, and their effects on single and 5pulse stimulated dopamine release monitored using the technique of fast cyclic voltammetry. Caffeine at 10 or 100µM had no significant effect on single pulse stimulated dopamine release. However 100µM caffeine caused a significant peak increase in 5pulse stimulated dopamine release. Both 1 and 30µM MDMA gave rise to a significant increase in both single and 5-pulse dopamine release and reuptake. A combination of 100µM caffeine and 1 or 30µM MDMA did not significantly enhance the effects of MDMA on single or 5pulse dopamine release and reuptake when compared to that applied alone. Utilizing single action potential dependent dopamine release, these results do not demonstrate a caffeine-enhanced MDMA-induced dopamine release.

Adenosine A1 receptor-mediated inhibition of dopamine release from rat striatal slices is modulated by D1 dopamine receptors.

Dopamine release is regulated by presynaptic dopamine receptors and interactions between adenosine and dopamine receptors have been well documented. In the present study, dopamine release from isolated striatal slices from Wistar rats was measured using fast cyclic voltammetry. Single-pulse stimulation (0.1 ms, 10 V) was applied every 5 min over a 2-h period. Superfusion with the adenosine (A)(1) receptor agonist N(6)-cyclopentyladenosine (CPA), but not the A(2) receptor agonist 3-[4-[2-[[6-amino-9-[(2R,3R,4S,5S)-5-(ethylcarbamoyl)-3,4-dihydroxy-oxolan-2-yl]purin-2-yl]amino]ethyl] phenyl]propanoic acid (CGS 21680), inhibited dopamine release in a concentration-dependent manner (IC(50) 3.80 x 10(-7) m; n = 10). The dose-response curve to CPA was shifted to the right (IC(50) 6.57 x 10(-6) m; n = 6, P < 0.05 vs. control) by the A(1) receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). Neither the D(1) agonist 6-chloro-APB nor the D(1) antagonist R-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3- benzazepine-7-ol (SCH 23390) altered dopamine release on their own. However, SCH 23390 (3 microm) significantly attenuated the response to CPA (IC(50) 1.44 x 10(-5) m; n = 6, P < 0.01 vs. control). Furthermore, the inhibitory effect of CPA was significantly increased in the presence of 6-chloro-APB (1 microm). In radioligand binding experiments, CPA interacted with high- and low-affinity states of [(3)H]DPCPX-lableled A(1) receptors. The high-affinity agonist binding to A(1) receptors was inhibited by the stable guanosine triphosphate analogue Gpp(NH)p. In contrast, neither the proportion nor the affinity of high-affinity A(1) receptors was altered by dopamine or SCH 23390. These results provide evidence that the inhibition of dopamine release by adenosine A(1) receptors is dependent, at least in part, on the simultaneous activation of D(1) dopamine receptors. While the mechanism underlying this interaction remains to be determined, it does not appear to involve an intramembrane interaction between A(1) and D(1) receptors.

Immunization of colorectal cancer patients with modified ovine submaxillary gland mucin and adjuvants induces IgM and IgG antibodies to sialylated Tn.

Tn and sialylated Tn (sTn) are blood group-related epitopes expressed on mucins of colon carcinoma and other epithelial tumors and are, therefore, potential targets for immunological control. We have immunized 20 colorectal cancer patients at high risk for recurrence with a vaccine consisting of partially desialylated ovine submaxillary gland mucin (modified OSM) which contains both Tn and sTn determinants. Six patients were treated with modified OSM alone (group 1), eight patients were treated with modified OSM and the immunological adjuvant DETOX (group 2), and six patients were treated with modified OSM and Bacillus Calmette-Guérin (group 3). Pre- and postvaccination sera were tested by enzyme-linked immunosorbent assay and dot blot immune stains for antibodies reactive with modified OSM. Antibody titers increased in 4 of 8 patients immunized with modified OSM and DETOX, in 5 of 6 patients immunized with modified OSM and B. Calmette-Guérin, and in 0 of 6 patients receiving modified OSM without adjuvant. The specificity of induced IgM and IgG antibodies was confirmed by demonstrating reactivity with OSM, bovine submaxillary mucin, and synthetic glycoconjugates sTn-human serum albumin (HSA) and Tn-HSA in enzyme-linked immunosorbent assay and immune stains. Median IgM pre-postvaccination reciprocal titers were 20/80 for Tn-HSA and 10/320 for sTn-HSA. Low level IgG antibody titers against sTn-HSA were detected after vaccination in 7 patients. Toxicity was limited to inflammatory skin reactions at the site of vaccination resulting from the adjuvants. No inflammatory infiltrates were seen in the skin when the modified OSM vaccine was administered in the absence of an immunological adjuvant. These results demonstrate that sTn and Tn can be recognized by the human immune system and that vaccines containing these structures can be administered safely with immunological adjuvants. Attempts to augment the immunogenicity of these carbohydrate antigens by covalent attachment to immunogenic carrier proteins and the use of more potent immunological adjuvants are now being pursued.

Multiinstitutional phase II trial of intensive combination chemoimmunotherapy for metastatic melanoma.

PURPOSE: To evaluate the activity and toxicity of combined high-dose cisplatin, dacarbazine (DTIC), and tamoxifen chemotherapy and high-dose bolus interleukin-2 (IL-2) in patients with metastatic melanoma. PATIENTS AND METHODS: Patients with metastatic melanoma, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and normal organ function were enrolled onto this multiinstitutional Cytokine Working Group trial. Patients received intensive chemoimmunotherapy consisting of cisplatin (50 mg/m2) and DTIC (350 mg/m2) intravenously (IV) on days 1 to 3 and 43 to 45, IL-2 600,000 IU/kg IV every 8 hours on days 12 to 16 and 26 to 30 (maximum, 28 doses), and tamoxifen 20 mg orally each day. Patients were evaluated for response at day 63 of each cycle, and responding patients were given a second cycle of therapy beginning on day 71 to 85. RESULTS: Thirty-eight patients were entered onto this study. Toxicities were as expected for the chemotherapy and immunotherapy components of this regimen. Overlapping toxicity consisted primarily of thrombocytopenia (76% of patients required platelet transfusions), neutropenia, anemia, fatigue, and weight loss. Despite these cytopenias, bleeding and infectious complications were rare. There were no treatment-related deaths. Three patients achieved a complete response (CR; 8%), and 13 achieved a partial response (PR). The overall objective response rate was 42% (95% confidence interval [CI], 26% to 58%). Six additional patients had greater than 50% tumor reduction at day 63, which did not persist until a subsequent evaluation. The median duration of response was 5 months (range, 2 to 20+), and the median survival duration was 11 months. CONCLUSION: This intensive treatment regimen appears to possess activity in metastatic melanoma comparable, but not superior, to that of other less intensive cisplatin- and IL-2-based chemoimmunotherapy regimens. Although the toxicity and complexity of this regimen make it unsuitable for phase III testing and impractical for more widespread use, the results of this study support a potential favorable interaction between IL-2 and chemotherapy in this disease and highlight the need for appropriately designed phase III trials.

Phase IB clinical trial of anti-CD3 followed by high-dose bolus interleukin-2 in patients with metastatic melanoma and advanced renal cell carcinoma: clinical and immunologic effects.

PURPOSE: To determine the maximum-tolerated dose (MTD) of an anti-CD3 antibody, OKT3, in combination with high-dose interleukin-2 (IL-2), and to determine whether OKT3 can enhance the expansion of CD3+, CD25+ (IL-2 receptor alpha [IL-2R alpha])-expressing T cells in the peripheral blood of patients with advanced melanoma and renal cell carcinoma receiving high-dose IL-2. PATIENTS AND METHODS: We performed a phase IB trial of a murine monoclonal anti-CD3 antibody (OKT3) with high-dose IL-2 in patients with advanced melanoma and renal cell carcinoma. Fifty-four patients were enrolled, with cohorts of 10 or more patients receiving escalating doses of OKT3 at 75, 200, 400, and 600 micrograms/m2 on day 1 followed by IL-2 at an initial dose 0.45 and then 1.33 mg/m2 every 8 hours on days 2 through 6 and 16 through 20 (maximum, 28 doses). An additional cohort of 14 patients received high-dose IL-2 (1.33 mg/m2 per dose) alone. Circulating CD3+, CD25+ cells were monitored before therapy and following the initial week of IL-2. RESULTS: A total of 68 patients were enrolled. The MTD for OKT3 was defined as 400 micrograms/m2 based on a reduction in the number of IL-2 doses that could be administered. Increases in CD3+, CD25+ cells were observed within all cohorts; however, the increase was not OKT3 dose-dependent. On the other hand, we found that 60% (nine of 15) of patients tested at OKT3 dose levels of 200, 400, and 600 micrograms/m2 had increases in serum sCD25 (soluble IL-2R alpha) to more than 100,000 U/mL, while none of 10 patients who received IL-2 alone or with OKT3 at the 75-micrograms dose had increases greater than 60,000 U/mL. Of 29 patients with renal cell carcinoma who received OKT3 with IL-2 (1.33 mg/m2), there were three objective tumor responses (all partial responses). In the 16 patients with melanoma who received OKT3 plus IL-2, there was a single objective response (complete response). CONCLUSION: The doses of OKT3 administered on this schedule failed to enhance significantly the number of circulating CD3+, CD25+ T cells and did not appear to increase the antitumor activity of IL-2 alone, which underscores the need for other approaches to enhance the efficacy of IL-2 therapy.

Prospective randomized trial of lisofylline for the prevention of toxicities of high-dose interleukin 2 therapy in advanced renal cancer and malignant melanoma.

The therapeutic application of high-dose interleukin (IL) 2 in human malignancy is limited by severe multiorgan toxicities that are mediated, in part, by tumor necrosis factor (TNF) and IL-1. CT1501R (lisofylline; LSF) is one of several methyl xanthine congeners that inhibit the effects of TNF by the interruption of specific signal transduction pathways. This randomized, placebo-controlled trial was designed to assess the activity of LSF in reducing the toxicities of high-dose IL-2 therapy. Fifty-three patients with metastatic renal cancer or malignant melanoma were treated with i.v. bolus IL-2, 600, 000 IU/kg every 8 h for 5 days (14 doses), followed by 9 days of rest and another 5-day course of IL-2. Patients were randomly assigned to LSF, 1.5 mg/kg i.v. bolus, or placebo every 6 h during IL-2 therapy. All patients were to be treated to individual maximum tolerance of IL-2 at the intensive care unit level of support. The end points for statistical analysis were the number of IL-2 doses administered during the first cycle of treatment (maximum, 28) and the toxicities experienced by each group after the first 8 planned IL-2 doses. There was no difference between the LSF and placebo groups in the mean number of IL-2 doses tolerated in the entire first cycle of therapy (19.6 +/- 5.4 versus 19.5 +/- 5.8, P = 0.86) or in the first or second 5-day course of IL-2. The only significant difference in toxicities occurring through the eighth dose of IL-2 was in the maximum elevation of serum creatinine (mean, 1.7 +/- 0.8 for placebo versus 1.5 +/- 0.6 mg/dl for LSF, P = 0.013). A Monte Carlo analysis of major toxicities over the first 14-dose course of therapy showed a statistically significant difference favoring the LSF-treated group (P = 0.025). LSF was well tolerated, associated only with mildly increased nausea (P = 0.006 after eight IL-2 doses, but not significant for the entire first cycle). The antitumor activity was comparable in both groups (objective responses, 2 of 28 with LSF versus 4 of 24 with placebo). The mean peak plasma concentrations of LSF on days 1, 5, and 19 were 6.24, 3.83, and 5.04 micromol/liter, respectively. In conclusion, with this dose and schedule, LSF did not alter the toxicities of high-dose i.v. IL-2 sufficiently to impact the overall dose intensity of IL-2. Successful IL-2 toxicity modulation may require the use of higher doses of LSF, the development of agents with more potent anti-TNF activity, and/or combined modulating agents that function via distinct mechanisms to interrupt cytokine-mediated signaling.

Metastatic solid-pseudopapillary tumour of the pancreas: clinico-biological correlates and management.

Solid-pseudopapillary tumour of the pancreas is a rare neoplasm of young women, currently categorised in the World Health Organization classification under exocrine pancreatic tumours. Increased awareness of this condition correlated recently with an apparent rise in incidence as well as recognition of more aggressive clinical courses. We describe two patients with solid-pseudopapillary tumour of the pancreas. A smaller, localised tumour in an unusually young white man was surgically excised with no evidence of recurrence after 2 years. The other case also had an uncommon presentation, with an aggressive course resulting in vascular encasement of the superior mesenteric bundle and aorta, and local involvement of the mesenteric lymph nodes. A literature review was carried out, and the main clinico-pathological features and strategies of treatment of solid-pseudopapillary tumour of the pancreas are presented. Pathological, genetic and molecular features distinguish solid-pseudopapillary tumours from pancreatic ductal adenocarcinoma. Furthermore, neuroendocrine differentiation can be found focally in occasional cases of solid-pseudopapillary tumour. Patients with localised disease are usually cured by surgery. Prolonged survival can be seen in the presence of distant metastasis, if such lesions are resected surgically. Chemotherapy and radiation therapy are used in rare cases when resection is not possible. No current chemotherapy regimens are considered standard in the treatment of this tumour. A rational chemotherapy protocol for such a rare tumour needs to consider its origin and clinical behaviour. However, the indolent clinical progression of solid-pseudopapillary tumours is similar to that of pancreatic neuroendocrine tumour.

The isolated major histocompatibility complex class I alpha3 domain binds beta2m and CD8alphaalpha dimers.

The MHC class I molecule plays a crucial role in cytotoxic lymphocyte function. The heavy chain of the MHC class I molecule can form many non-covalent interactions with other molecules on multiple domains and surfaces. We have generated an isolated alpha3 domain of a murine MHC class I molecule and evaluated the contribution of this domain to binding with the MHC class I light chain, beta2m, and CD8. The alpha3 domain binds beta2m at a thousand-fold higher concentration than the whole MHC, and binds CD8alphaalpha with a dependence on the alpha3 CD loop. Our results are relevant for models of MHC folding and CD8-MHC function. The study of individual domains of complex molecules is an important strategy for understanding their dynamic structure and function.

A re-evaluation of changes in rat striatal D-2 dopamine receptors during development and aging.

High affinity binding of 3H-spiperone to D-2 dopamine receptors was measured in membrane fractions prepared from striata of male Sprague-Dawley rats aged 0.75-25 months. 3H-Spiperone bound with approximately 0.11 nM affinity in all age groups studied. The maximum number of D-2 receptors initially increased with age, peak adult levels being reached by 4 months of age. Receptor density declined by 33% over the next 7 months and no further loss of receptors was apparent between 11 and 25 months of age. Such a time-course suggests a loss of rat D-2 receptors that occurs, at least in this strain, earlier than has previously been appreciated, and appears to be in agreement with preliminary positron emission tomographic studies in living man.

Weekly doxorubicin in the treatment of patients with AIDS-related Kaposi's sarcoma. AIDS Clinical Trials Group.

Fifty-three patients with AIDS-related Kaposi's sarcoma and no previous treatment with cytotoxic chemotherapy enrolled in a phase II multicenter study to evaluate the safety and efficacy of weekly doxorubicin treatment. Doxorubicin was given intravenously at a dose of 15 mg/m2. Patients were stratified for purposes of analyses by tumor burden and coexistence of HIV-associated signs and symptoms; stratum I included patients with cutaneous disease alone and no symptoms, and stratum II included patients with visceral disease, tumor-associated edema, a previous opportunistic infection, or systemic symptoms. Fifty-one patients were evaluable for toxicity and 50 for tumor response. Five patients had a partial response (10%); 32, a minor response (64%); 12, no change (24%); and one, progression (2%) as the best measurable response. Partial response durations ranged from 4 to 14 weeks. Fifteen patients subsequently showed progression while on treatment. A significantly greater number of patients in stratum I (20.1%) had a partial response compared with those in stratum II (0%, p = 0.009). The major toxicities included nausea (37%), stomatitis (9.8%), mucositis (13.7%), and moderate to severe neutropenia (71%). Neutropenia was dose limiting and resulted in discontinuation of doxorubicin in 18% of the patients. Two patients developed cardiac toxicity. In conclusion, doxorubicin treatment induced relatively few tumor responses and remission durations were short. Treatment was limited by a high rate of toxicity.

New substituted 1-phenyl-3-benzazepine analogues of SK&F 38393 and N-methyl-thienopyridine analogues of dihydroxynomifensine with selective affinity for the D-1 dopamine receptor in human post-mortem brain.

3H-SCH 23390 and 3H-spiperone were used to label D-1 and D-2 dopamine receptors, respectively, in human post-mortem brain. SK&F 82958 and SK&F 77434, new substituted 1-phenyl-1H-3-benzazepines, showed selective affinity for the D-1 receptor. While S- and R- enantiomers of dihydroxynomifensine showed only weak stereoselective affinity for the D-1 receptor, the thieno [2,3-c]-and thieno [3,2-c]- analogues SK&F 89145 and SK&F 89641 showed selective D-1 affinity comparable to that of the benzazepines. These novel agents provide new information on structure-affinity relationships and D-1 receptor topography, and constitute new tools for functional studies.

Agonist and antagonist interactions with D1 dopamine receptors: agonist-induced masking of D1 receptors depends on intrinsic activity.

The effects of agonist and antagonist compounds on the equilibrium binding of the D1 antagonist ligand [3H]SCH 23390 were examined in membranes from the striatum of the rat. The antagonist SK&F 83566 interacted with D1 receptors in the manner of a competitive antagonist, causing a decrease in the affinity of the binding of [3H]SCH 23390, without altering the maximum number of binding sites (Bmax). The interaction of agonist compounds with the D1 receptor appeared to be more complex. The drug SK&F 75670, a weak partial agonist, also acted competitively at D1 sites. However, agonists with moderate (SK&F 38393, CY 208-243) or full (dopamine) intrinsic activity to stimulate adenylate cyclase, interacted with D1 binding sites in a mixed competitive/non-competitive manner, causing both a decrease in ligand affinity and a decrease in Bmax. The benzazepine analogue, which also has full agonist activity, SK&F 82958, only caused a reduction in Bmax. Furthermore, there was a positive relationship between the intrinsic activity of agonists and the magnitude of the reductions in Bmax which they induced. In the presence of the GTP analogue, Gpp(NH)p, CY 208-243 no longer caused an apparent reduction in the number of receptors. These data suggests that the apparent loss of D1 receptors, induced by agonists, may result from an interaction with a guanine-nucleotide sensitive, high affinity agonist binding site and that the degree of interaction with this site depends on the intrinsic D1 activity of the agonist.

Dopamine-induced reduction in the density of guanine nucleotide-sensitive D1 receptors in human postmortem brain in the absence of apparent D1: D2 interactions.

The effects of dopamine and guanine nucleotides on the binding of the D1 dopamine receptor antagonist ligand [3H]SCH 23390 were examined in membranes prepared from putamen, caudate and nucleus accumbens of human postmortem brain. Dopamine induced a concentration-dependent decrease in the apparent maximum number of binding sites (Bmax) in each brain region studied, and displaced binding in a biphasic manner consistent with the presence of both high and low affinity states of the D1 receptor; the GTP analogue Gpp(NH)p transformed this biphasic displacement to a monophasic pattern consistent with a shift of high affinity sites to a low affinity state. However, the selective D2 antagonist eticlopride did not reverse the action of dopamine to decrease Bmax. These data suggest that dopamine decreases Bmax for D1 receptors through a high affinity, guanine nucleotide-sensitive agonist binding site, but fail to reveal D1:D2 interactions at this synaptic level.

Agonist and antagonist properties of benzazepine and thienopyridine derivatives at the D1 dopamine receptor.

Nine structurally related 1-phenyl-1H-3-benzazepine derivatives and two thienopyridines were tested for agonist and antagonist properties at the adenylate cyclase-coupled D1 dopamine receptor in homogenates of the striatum of the rat. The benzazepines SK&F 77434 and SK&F 82958, both of which contain a catechol ring, were agonists; the intrinsic activity of SK&F 77434 was similar to that of SK&F 38393, whereas SK&F 82958 was a full agonist. The remaining benzazepines inhibited the stimulation of adenylate cyclase by dopamine. Antagonist potency depended on the nature of the substituent at position 7 of the benzazepine molecule, 7-halogen compounds being the most potent. The Ki values, obtained from analysis of the antagonism of dopamine-stimulated adenylate cyclase, were significantly correlated with the Ki values for displacement of D1 ligands in binding experiments. Furthermore, antagonist activity of the resolved racemic benzazepine SK&F 83566 resided almost exclusively in the R-enantiomer. The thienopyridine derivatives SK&F 89641 and SK&F 89145 were partial agonists with greater efficacies than SK&F 38393.

Functional coupling of a recombinant human 5-HT5A receptor to G-proteins in HEK-293 cells.

1. We have cloned, expressed and pharmacologically characterized the Human 5-HT5A receptor. 2. We have shown that ligand activation of the Human 5-HT5A receptor results in functional coupling to G-proteins in HEK-293 cells. 3. Stimulation of the receptor with 5-CT (5-carboxamidotryptamine) resulted in a dose-dependent increase in the % [35S]-GTPgammaS binding over the basal level. This is the first study to describe such G-protein activation for the Human 5-HT5A receptor in any cell. 4. A dose-dependent inhibition of cyclic AMP accumulation was observed in the recombinant Human 5-HT5A receptor cell line, suggesting a functional coupling to a G alpha i, G-protein in the HEK-293 cell line. 5. A ligand-stimulated reduction in the detectable level of the catalytic domain of protein kinase A (PKA) in nuclear extracts isolated from Human 5-HT5A expressing cells was observed. This observation was consistent with the reduction in the level of cyclic AMP accumulation, in response to receptor activation.

Association of intellectual impairment, negative symptoms, and aging with tardive dyskinesia: clinical and animal studies.

It is not known why some schizophrenic patients receiving long-term neuroleptic treatment develop abnormal involuntary orofacial movements, while others do not. Schizophrenic patients with orofacial dyskinesia were found to be more intellectually impaired, more likely to show negative symptoms, and older than those without such movements. These features are characteristic of the "defect state," wherein structural brain changes may be demonstrable. Prolonged long-term neuroleptic treatment of young rats was associated with late-onset orofacial movements; however, such movements occurred spontaneously in untreated senescent rats. Structural brain changes consequent to aging and disease processes may be associated with the emergence of orofacial dyskinesia, even in the absence of exposure to neuroleptics. These movements do not appear to have their basis in striatal dopamine receptor supersensitivity.

Effects of the putative D-1 antagonist SCH 23390 on stereotyped behaviour induced by the D-2 agonist RU24213.

The effects of the putative selective dopamine D-1 antagonist benzazepine SCH 23390 and of the selective dopamine D-2 antagonist Ro22-2586 on stereotypy induced by the selective D-2 agonist RU24213 were compared. RU24213 (0.5-15 mg/kg) dose-dependently induced stereo-typed behaviour characterised by continuous downward sniffing and locomotion. These responses were antagonised, as expected, by 40-200 micrograms/kg Ro22-2586, but surprisingly blocked by 40-200 micrograms/kg SCH 23390. The selectivities of these compounds for dopamine receptor subtypes were verified in terms of their relative abilities to displace the in vitro binding of 3H-piflutixol to striatal D-1 receptors and of 3H-spiperone to D-2 receptors. As SCH 23390 fails to influence D-2 mediated prolactin secretion or emesis in vivo, there appears to be no significant formation of an active metabolite of SCH 23390 with D-2 antagonist activity. Because SCH 23390 has some affinity for 5-hydroxytryptamine receptors, any effect on the serotonergic behavioural syndrome induced by 10 mg/kg 5-methoxy-N,N-dimethyltryptamine was also studied. The serotonergic responses of hind limb abduction, reciprocal forepaw treading and Straub tail were unaltered after 40-200 micrograms/kg SCH 23390, indicating no significant 5-HT blockade or non-specific depressant action at these doses which might influence the expression of stereotypy. Thus, these data are consistent with blockade of tonic D-1 dopaminergic activity that may influence the expression of behaviours initiated by D-2 dopaminergic stimulation.

Synthesis of D-hexos-5-uloses by novel in situ hydrolysis of epoxides derived from 6-deoxyhex-5-enopyranosides.

[reaction: see text] Epoxides derived from 2,3, 4-tri-O-protected-6-deoxyhex-5-enopyranosides are hydrolyzed in situ to ultimately give novel protected-D-hexos-5-ulose derivatives (sugar 1,5-dicarbonyls, 5-ketohexoses) in moderate to high yields. The products adopt a bicyclic structure (1,6-anhydropyranos-5-ulose) in solution with the pyranose ring in (4)C(1) conformation. The methodology has been used to prepare D-xylo-hexos-5-ulose (5-ketoglucose), a synthetic precursor to 1-deoxynojirimycin and a possible intermediate in the biosynthesis of inositols.

20th-century advances in drug therapy in oncology--Part. II.

Ongoing research in cancer therapy has led to the development of antineoplastic agents which target specific components of the cell cycle. In Part II of this series, we discuss agents which target the mitotic mechanism by inhibiting microtubules. Although many of these agents are being shown to have multiple effects, the Vinca alkaloids and the taxanes are known as antimitotic drugs. They are among the most important anticancer agents currently available, and because of their unique mechanisms, can be combined with a wide variety of other antineoplastic agents in a spectrum of diseases. In addition, in part II, we are discussing agents that target DNA and prevent replication and thus cell growth by inhibiting the enzymes which protect DNA during replication, the topoisomerases. These drugs, too, have unique mechanisms of action and have become major components of combination regimens. The topoisomerase I inhibitors are new drugs derived from an older parent drug, and their full possibilities are still being explored.