DailyUpdates 29th April 2004: Cancer pain affects over 3 million people in the US alone. The treatment of this condition, whether it is due to bone metastasis or a result of the use of cytotoxic therapies is challenging. Researchers from McGill University have now demonstrated that ethosuximide, an anti-epileptic and relatively selective T-type calcium channel blocker, is highly effective in reversing neuropathic pain caused by the commonly employed cytotoxics paclitaxel or vincristine. This contrasted with the limited efficacy afforded to morphine and opens up new avenues for clinical and drug development approaches to this area of oncology. Cancer pain represents a large and unmet market. The condition can be associated with the cancer itself or with conventional cancer treatments such as chemotherapy or surgery, and it affects over 3 million people in the US alone. Currently, there is a vast range of drugs used in the treatment of cancer pain including opioids, NSAIDs, antidepressants and anticonvulsants, yet most physicians consider morphine to be the current gold standard. 

Cancer pain when associated with metastatic progression to the bone is chronic, consisting generally of ongoing spontaneous pain, and breakthrough pain occurring as a result of movement or weight bearing on the affected limb. Whilst ongoing pain may respond relatively well to opiates, breakthrough pain remains particularly difficult to control even with high doses. Considerable effort is currently being placed on developing models of metastatic bone pain and in a recent editorial produced by LeadDiscovery, the use of such a model has demonstrated the therapeutic potential of COX-2 inhibitors. In particular Novartis' Lumiracoxib has been shown to attenuate the mechanical hyperalgesia associated with intra-tibial injection of cancer cells (click here for the editorial).

Just as the identification of therapeutics able to treat metastatic pain would be enormous clinical use, so to would the discovery of agents that can limit the pain associated with many cytotoxics. Cytotoxics represent a mainstay of cancer therapeutics and of the five major cytotoxic classes, vinca alkaloids, which include the taxanes, represent the largest in terms of sales. BMS's Taxol (paclitaxel) once dominated not only the class but also the cytotoxic market as a whole. However, because of its patent expiry, it has lost its leading position to its rival drug, Aventis's Taxotere (docetaxel). The entry of generic and reformulated paclitaxel onto the market will is further eroding the market for Taxol. Pain is a frequent problem of paclitaxel and overcoming this problem would significantly advance the taxanes as a class of cytotoxic agent. Studies in rodents have demonstrated that paclitaxel causes neuropathic pain beginning within days and lasting for several weeks. Although treatment causes neurodegeneration at high doses, neurogenic pain remains evident at lower doses in the absence of nerve damage. Hyperalgesia appears to be mediated by protein kinase C epsilon and protein kinase A. Although these findings provide insight into the mechanism of taxol-induced painful peripheral neuropathy that may lead to the development of effective therapeutics, there are currently no generally accepted strategies for limiting the pain associated with cytotoxic agents. In their May Pain journal article, Flatters & Bennet report that ethosuximide reverses paclitaxel- and vincristine-induced painful peripheral neuropathy.

The McGill University researchers reported that paclitaxel-induced pain was relatively resistant to opioid therapy in their rodent model. At a dose 8 mg/kg, morphine had only a partial effect on mechanical allodynia/hyperalgesia. In contrast, ethosuximide, an anti-epileptic and relatively selective T-type calcium channel blocker, elicited a near complete reversal of mechanical allodynia/hyperalgesia. Repetitive dosing with ethosuximide showed a dose-related consistent reversal of mechanical allodynia/hyperalgesia with no evidence of tolerance. Ethosuximide also reversed paclitaxel-induced cold allodynia and vincristine-induced mechanical allodynia/hyperalgesia. These data suggest that T-type calcium channels may play a role in chemotherapy-induced neuropathy and moreover identify ethosuximide as a new potential treatment for chemotherapy-induced pain. 

Source: http://www.leaddiscovery.co.uk/PubMed-dailyupdates.html 

DailyUpdates 29th April; for a full abstract of the original papers see 
Pain. 2004 May;109(1-2):150-61. 

In this edition of DailyUpdates, LeadDiscovery also highlights the antiproliferative effect of nitrosulindac (NCX 1102) on human bladder carcinoma cell lines...anxiety and cognition in histamine H3 receptor-/- mice.5-Lipoxygenase inhibitors with histamine H(1) receptor antagonist activity...and much more.