14 Gemcitabine was developed in Dr Hertel's lab at Eli Lilly and Company during the early 1980s. It was meant to be an antiviral drug, however testing revealed it attacked leukaemia cells. Further research indicated it was effective against pancreatic cancer as a standalone drug. It also became used with Cisplatin to treat metastatic cancer. As is often the case it was registered for use in other countries before the USA where it was developed. Gemcitabine works by being incorporated into DNA as a faulty base. The drug masks itself from cellular repair mechanisms by allowing normal bases to be incorporated alongside the drug. The faulty base causes an irreparable error that inhibits further DNA synthesis and hence cell death is inevitable. Intravesical gemcitabine was initially reported as a treatment option for BCG-refractory non-muscleinvasive bladder cancer patients by a group led by Dr Dalbagni in 2002. Larger studies followed after 2010 initially by Dr Di Lorenzo. The drug has become recognised as an effective agent with relatively low toxicity. Docetaxel is another agent that has been used for chemohyperthermia therapy in the bladder. It has not been so widely studied as Mitomycin and Gemcitabine. Docetaxel was patented in 1986 and became available clinically in 1995. It is one of a family of drugs known as taxanes. Docetaxel is a more potent semisynthetic derivative of paclitaxel, derived from extracts of the leaves of the European yew tree (Taxus baccata). The cytotoxic activity of docetaxel is exerted by promoting and stabilising microtubule assembly, while preventing physiological microtubule disassembly. This leads to inhibition of mitotic cell division between metaphase and anaphase. The accumulation of microtubules also induces apoptosis though this is not its main mechanism of action. Docetaxel has been associated with Gemcitabine in combination for chemohyperthermia. Other drugs which have been shown to be efcacious in supercial bladder cancer include Doxorubicin, Epirubicin, and Valrubicin which are anthracycline antibiotics. They do not seem to have been used in hyperthermic studies. A drug known as EO9 or Apaziquone initially showed superior outcomes to Mitomycin and Gemcitabine, but the drug seems to have died a phase II death. Etoposide, another drug used for intravesical chemotherapy, actually has reduced efcacy when combined with heat. The role of immunotherapy deserves a mention at this point following the pioneering work of Professor Lamm in the 1970’s which saw chemotherapy for the bladder displaced by BCG. I invoked the name of Imhotep from 2600 BC in my previous article on the history of hyperthermia. Imhotep induced infection with incision and poultice to treat tumours. The immunotherapy brigade saw this as an immune response rather than from the fever induced. William Coley and his Toxin were also thought to be efcacious from an immune response rather than a thermal effect. In 1929 a study on cadavers showed that those infected with tuberculosis had a lower incidence of cancer compared with control studies. Who ever thought that TB was useful in health instead of a scourge? Research exploded in the early seventies on BCG therapy for various cancers starting with melanoma and rapidly encompassing other tumours. Unfortunately, just like hyperthermia nearly died an ignoble death, BCG immune therapy crashed as it just did not work except in bladder cancer. Lamm surmised that “it may simply be that bladder cancer is the ideal condition for the application of this immunotherapy.” BCG has remained the stalwart of treating recurrent supercial bladder cancer through into current times though cracks are starting to show in its foundations as hyperthermia therapy research gains traction. BCG not only medically but economically is coming under pressure. The low cost and therefore low protability of BCG has resulted in recurrent shortages that threaten both bladder cancer patients and children at risk for tuberculosis and other serious infections. BCG has been hung by its own petard as its low cost and therefore low protability mean less enthusiasm for its manufacture. Everyone involved in intravesical therapy today knows of the vagaries of BCG availability. Perhaps recombinant technologies will lead to a revival of its production as prots once again can be realised more readily for the medical industry. Professor Donald Lamm of Phoenix, Arizona UROLOGY, URO-ONCOLOGY AND SEXOLOGY UPDATE
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