8-Cl-adenosine is an active metabolite of 8-Cl-cAMP responsible for its in vitro antiproliferative effects on CHO mutants hypersensitive to cytostatic drugs

8-Cl-cAMP has been undergoing clinical trials as a potential chemotherapy agent, but there is much discussion in the literature as to whether the active agent is 8-Cl-cAMP itself, or its major metabolite, 8-Cl-adenosine. 8-Cl-cAMP is susceptible to the action of serum enzymes such as phosphodiesterases, and its metabolism when administered to cancer patients raises questions as to the mechanism of action of 8-Cl-cAMP. The stability of 8-Cl-cAMP when incubated with serum, and the effects of both 8-Cl-cAMP and 8-Cl-adenosine on the proliferation of variant lines of CHO cells hypersensitive to 8-Cl-cAMP were investigated. A solid-phase extraction (SPE) purification protocol and the HPLC method previously developed were used to determine 8-Cl-cAMP and 8-Cl-adenosine. Heat treatment of serum inactivated the enzymes in the culture medium responsible for activating 8-Cl-cAMP. Under these conditions 8-Cl-cAMP remained stable and there were no traces of its metabolite, 8-Cl-adenosine. Cell culture experiments showed that 8-Cl-cAMP only affected cell growth in medium that contained untreated serum. In contrast, 8-Cl-adenosine was shown to be growth inhibitory in medium containing either heat-treated or untreated serum. HPLC analysis of the culture medium from the cell culture experiments supported the hypothesis that 8-Cl-cAMP was only effective in inhibiting cell growth after metabolism to 8-Cl-adenosine. Thus further studies of this drug and its mechanism of action should focus on 8-Cl-adenosine.     

Bone or cartilage invasion by advanced head and neck cancer: intra-arterial supradose cisplatin chemotherapy and concomitant radiotherapy for organ preservation.

BACKGROUND: Invasion of bony or cartilaginous structures by advanced upper aerodigestive tract cancer has been considered an indication for surgery on the basis of historic experience of poor responsiveness to radiation therapy. At University of Tennessee-Memphis, patients with advanced head and neck cancer have been treated on a protocol of concomitant intra-arterial (targeted) cisplatin and conventional radiation therapy. OBJECTIVE: To compare the efficacy, in terms of disease control and survival, of this protocol in patients with T4 squamous cell cancers and invasion of bony or cartilaginous structures (group 1; n = 45) vs those with T4 disease but no bone or cartilage involvement (group 2; n = 90). DESIGN: Subset analysis of protocol database and retrospective chart review. METHODS: Treatment consisted of 4 weekly intra-arterial infusions of cisplatin (150 mg/m(2) per week), with simultaneous systemic neutralization by intravenous sodium thiosulfate (9 mg/m(2)), and concurrent radiation therapy at 180 rad (1.8 Gy) or 200 rad (2 Gy) per fraction to a planned total of 6600 to 7400 rad (66-74 Gy) to the primary site or overt nodal disease. Presence of bone or cartilage invasion was established by review of tumor diagrams of clinical findings and computed tomography or magnetic resonance imaging reports. RESULTS: Of 135 patients who had T4 disease and a minimum follow-up of 9 months (median, 40 months), 45 had clinical or radiologic evidence of bone (n = 29: mandible, 12; maxilla, 9; sphenoid, 3; hyoid, 6) and/or cartilage (n = 18: thyroid, 16; cricoid, 4) invasion (some patients had involvement of more than 1 site). The rate of complete response in group 1 (66.7%) was not significantly different from that in group 2 (71.1%) (chi(2) test, P = .79). The 2-year overall actuarial survival for group 1 (46.3%; 95% confidence interval, 30.3%-62.3%) was not significantly different (generalized Wilcoxon test, P = .36) from that of group 2 (36.9%; 95% confidence interval, 25.5%-48.4%). A marked trend was noted for higher response rates in cases of cartilage invasion (81.2%) than in those with bone invasion (58.6%) (P = .15). CONCLUSION: Equivalent efficacy of treatment in the 2 groups suggests that targeted chemoradiation can be a definitive therapeutic option in patients with advanced head and neck cancer invading bony or cartilaginous structures.     

Analysis of risk factors predictive of distant failure after targeted chemoradiation for advanced head and neck cancer.

BACKGROUND: Distant metastasis (DM) is the most common mode of recurrence among patients with advanced head and neck carcinoma treated with intra-arterial cisplatin and radiotherapy (RADPLAT). OBJECTIVE: To identify which patients are at greatest risk for DM and would benefit the most from new strategies designed to treat occult metastases. METHODS: Between 1993 and 1999, 250 patients with advanced head and neck cancer were treated by RADPLAT. Excluded from the analysis were 10 patients who either did not complete the protocol or were unavailable for follow-up and 39 patients with persistent disease or local recurrence. The incidence and the risk factors for DM in these patients were evaluated in a model that included the following factors: age, T and N classification, site of tumor, histologic grade, number (0, 1, or >1) and position (high vs low) of neck levels involved, and bilateral nodal disease. Multiple stepwise logistic regression was used for the analysis. RESULTS: In a univariate analysis, the following variables correlated to DM: N classification (P =.02), site of tumor (P =.01), lower neck nodes (P =.002), number of neck levels involved (P =.001), and bilateral nodal disease (P =.02). In a multivariate analysis, the most significant risk factors for DM were the number of neck levels involved and the site of the primary tumor (P<.001). The highest odds ratios for DM were among patients with multiple levels of nodal involvement (3.17) and patients with hypopharyngeal carcinoma (2.8). CONCLUSIONS: Patients with more than 1 level of clinical nodal involvement and patients with hypopharyngeal carcinoma have the highest risk of developing DM as the initial site of failure and would benefit most from treatment strategies that address occult distant disease.     

Level V in therapeutic neck dissections for papillary thyroid carcinoma

Neck dissection for papillary thyroid carcinoma (PTC) is the standard of care for patients with clinical evidence of regional metastases. However, the extent of neck dissection is debatable. The purpose of the current study was to develop evidence‐based recommendations for when to include level V, or 1 of its sublevels, among patients with PTC undergoing neck dissection. A literature review of all studies evaluating the occurrence of metastases in level V in patients with regional metastases from PTC undergoing neck dissection was performed. Occurrence of metastases at level V is low in most series (5% to 10%), although a wide range was noticed. In cases in which metastases were found at level V, they occurred almost exclusively at sublevel VB. Sublevel VA was rarely, if ever, involved with metastatic lymph nodes. However, only recently have investigators begun to specify which sublevels of level V are at risk. Therapeutic dissection of level V is indicated when there is clinical evidence of disease involving this zone. Elective dissection of sublevel VB is indicated when there is involvement of level IV, or possibly multiple nodes at levels II and III. Under these circumstances, dissection of sublevel VB is indicated but sublevel VA may be spared. © 2012 Wiley Periodicals, Inc. Head Neck, 2013     

Differential control over cocaine-seeking behavior by nucleus accumbens core and shell

Nucleus accumbens (NAc) dopamine is widely implicated in mediating the reinforcing effects of drugs of abuse. However, the precise function of the NAc itself in drug self-administration has been difficult to establish. Here we show a neural double-dissociation of the behavioral processes that underlie cocaine self-administration in rats. Whereas selective excitotoxic lesions of the NAc core had only a minor effect on the acquisition of responding for cocaine under a standard schedule of continuous reinforcement, these lesions profoundly impaired the acquisition of drug-seeking behavior that was maintained by drug-associated conditioned reinforcers and assessed using a second-order schedule of cocaine reinforcement. In contrast, selective excitotoxic lesions of the NAc shell did not impair drug self-administration or the acquisition of cocaine-seeking, but they did attenuate the psychostimulant effects of cocaine. These results further our understanding of how the NAc controls drug-seeking and drug-taking behavior.     

The effects of excitotoxic lesions of the substantia innominata, ventral and dorsal globus pallidus on the acquisition and retention of a conditional visual discrimination: implications for cholinergic hypotheses of learning and memory

The effects of ibotenic acid-induced lesions of the ventral pallidum/substantia innominata region, the dorsal pallidum or both on the acquisition and retention of a conditional visual discrimination have been studied in the rat. Lesions of the ventral pallidum and large lesions of the dorsal and ventral pallidum severely impaired both the acquisition and retention of the conditional discrimination. Dorsal pallidal lesions had similar, but less marked effects. The same lesions also impaired the retention of a passive avoidance task, but had no effect on a conditioned taste aversion. Neurobiological investigations revealed that the lesions destroyed cholinergic neurons in the magnocellular nucleus basalis and caused reductions in cortical choline acetyltransferase activity of about 30-40%. Tract-tracing experiments indicated that the lesions destroyed, in particular, cholinergic neurons projecting to the frontal dorsolateral cortex and also those projecting to more posterior cortex, but not the occipital lobes. Contingency analysis of the behavioural, neurochemical and neuroanatomical data indicated that those animals with the largest decreases in choline acetyltransferase activity, or the largest areas of neuronal loss in the ventral and dorsal globus pallidus, were most impaired in the retention of the conditional discrimination. The results do not, therefore, indicate a simple relationship between cholinergic neuronal loss and the retention of response rules essential for performance of the task ("reference memory"). The relevance of the results to cholinergic hypotheses of learning and memory is discussed.