Bladder cancer mechanism

Docetaxel is a semisynthetic taxane derived from the European yew tree. Its mechanism of action, metabolism, and elimination are identical to those of paclitaxel. It is approved for use as second-line therapy in advanced breast cancer and non-small cell lung cancer, and it also has major activity in head and neck cancer, small cell lung cancer, gastric cancer, advanced platinum-refractory ovarian cancer, and bladder cancer. Its major toxicities are listed in Table 54-4. 

Some other aromatic amines such as benzidine and 4-aminobiphenyl are also carcinogenic to the bladder by the same mechanism. These amines have industrial uses and have been implicated in bladder cancer in exposed humans. 

Acute exposure of Chinese hamster ovary (CHO) cells or human bladder cancer MGH-U1 cells to hypoxia plus low pH (6.5-6.0), was cytotoxic in a time- and pH-dependent manner. Inhibition of glycolysis by incubation of CHO cells under hypoxic conditions in the absence of glucose at pH 7.0 led to a larger fall in cellular ATP and energy charge. A decrease in energy charge of the cells may contribute to loss of viability, but additional mechanisms appear to be involved (Rotin et al., 1986). 

Larotaxel (XRP-9881, RPR 109881A) 59 (Sanofi-Aventis) is undergoing Phase III trials in patients with advanced pancreatic cancer who had been previously treated with gemcitabine, as well as in combination with cisplatin to treat locally advanced/metastatic urothelial tract or bladder cancer.124 A Phase III trial for the treatment of advanced breast cancer has been completed. Larotaxel 59129>130 js a semi-synthetic derivative of 10-deacetyl baccatin III with a docetaxel-like side chain that has a low affinity for the P-glycoprotein drug efflux pump, an efflux mechanism that diminishes the effectiveness of the marketed drugs paclitaxel 60 and docetaxel. Importantly, this low affinity should enable larotaxel 59 to be effective in tumours resistant to paclitaxel 60... 

Intravesical instillation of BCG has been nsed to treat superficial bladder carcinoma and interstitial cystitis. Many reports have confirmed the efficacy of BCG in the treatment of transitional cell bladder cancers and have delineated its adverse effects (SEDA-12, 273) (SEDA-13, 278) (SEDA-15, 344) (SEDA-16, 375) (SEDA-17, 366) (SEDA-18, 328) (SEDA-20, 287) (SEDA-21, 328) (SEDA-22, 336). The exact mechanism of its antitumor activity is unknown, but live BCG provokes an inflammatory response that includes activation of macrophages, a delayed hypersensitivity reaction, and stimulation of T and B lymphocytes and natural killer cells. 

Evidence for the mechanism of bladder cancer derives from correlation of certain structural features of aromatic amines important in carcinogenecity, and knowledge of activation steps and metabolites obtained from laboratory animals73. Earlier studies revealed the biochemistry of the carcinogenic aromatic amines Questions remained as to whether binding to DNA or RNA was causally connected to carcinogenic action. 

Burin, G. J., Gibb, H. J., and Hill, R. N. (1995). Human bladder cancer Evidence for a potential irritation-induced mechanism. Food Chem Toxicol 33, 785-795. 

FIGURE 16.33 Molecular pathways in invasive urothelial carcinoma. (Adapted from Mitra AP, Qatar RH, Cote Rj. Molecular pathways in invasive bladder cancer new insights into mechanisms, progression, and target identification. I Clin Oncol. 2006 24 5552.)... 

Badawi, A.F., Mostafa, M.H., Probert, A., and O Connor, P.J. (1995) Role of schistosomiasis in human bladder cancer evidence of association, aetiological factors, and basic mechanisms of carcinogenesis. Eur. J. Cancer Prev., 4, 45-59. 

There is a broad range of mechanisms against these targets, such as specific cytokines, tumor cell expression of rejection antigens and inducing lymphocyte co-stimulatory molecules on tumor cells (vide infra). Non-specific approaches also exist, e.g. Bacille Calmet Guerrin vaccine (BCG), which elicits a T lymphocyte cell-mediated immune response, can be used not only to prevent tuberculosis but also to (non-specifically) prevent the recurrence of bladder cancer. 

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