Bone biology limitations

Garnero P, Dehnas PD. Measurements of biochemical markers methods and limitations. In Bhezikian JP, Raisz LG, Rodan GA, eds. Principles of bone biology. San Diego Academic Press, 1996 1277-91. 

In phase I clinical trials 47 patients, all of whom had previously failed standard treatments for solid tumors, received the drug in the UK, Italy, and Switzerland on three different schedules.123,124 Dose-limiting toxicities have been defined as bone marrow depression and diarrhea. The latter is treatable with loperamide. Signs of biological activity were seen. Notably one patient with metastatic pancreatic cancer showed a partial response (for 4 months) and two further patients, one with metastatic melanoma and one with bronchoalveolar carcinoma, also showed partial responses. In a phase I trial in combination with 5-FU, a partial response in breast cancer was observed.125 Furthermore, a reduction in tumor marker levels was observed in two patients, one with ovarian cancer, and one with colon cancer. Phase II studies have shown partial responses in cisplatin-resistant ovarian and nonsmall-cell lung cancer.126,127 The indications are that the profile of clinical activity is different and complementary to the mononuclear platinum agents. 

Thongh most (by volnme) of the human body is composed of soft materials snch as skin and mnscle, we wonld have limited abilities to eat, move, and protect onrselves were it not for hard biologies such as bone and teeth. From an indnstrial standpoint, hard tissne repair acconnts for roughly 20% of the multi-billion dollar biomaterials industry worldwide [4], with a projected growth rate of 7-12% annually. 

Artificial Soft Biologies. In addition to sutures, polymers are used for a number of biomedical applications, as illustrated in Figure 5.128. Polymers used for hard structural applications such as dentures and bones are presented in this figure, but will be described in the next section. In this section, we will concentrate on polymers for soft biological material applications and will limit the description to mechanical properties as much as possible. 

Azathioprine is a cytotoxic inhibitor of purine synthesis effective for the control of tissue rejection in organ transplantation. It is also used in the treatment of autoimmune diseases. Its biologically active metabolite, mercaptopurine, is an inhibitor of DNA synthesis. Mercaptopurine undergoes further metabolism to the active antitumour and immunosuppressive thioinosinic acid. This inhibits the conversion of purines to the corresponding phosphoribosyl-5 phosphates and hypoxanthine to inosinic acid, leading to inhibition of cell division and this is the mechanism of the immunosuppression by azathioprine and mercaptopurine. Humans are more sensitive than other species to the toxic effects of the thiopurines, in particular those involving the haematopoietic system. The major limiting toxicity of the thiopurines is bone marrow suppression, with leucopenia and thrombocytopenia. Liver toxicity is another common toxic effect. 

Potential interfering substances in a biological matrix include endogenous matrix components, metabolites, decomposition products, and in the actual study, concomitant medication. Whenever possible, the same biological matrix as the matrix in the intended samples should be used for validation purposes. For tissues of limited availability, such as bone marrow, physiologically appropriate proxy matrices can be substituted. Method selectivity should be evaluated during method development and method validation and can continue during the analysis of actual study samples. 

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