Tumour tissue

Clear identification of tumour-associated antigens would facilitate the production of monoclonal antibodies capable of selectively binding to tumour tissue. Such antibodies could be employed to detect and/or destroy the tumour cells. 

Whole IgG antibodies with a molecular weight of 150 kDa, are often unable to penetrate tumour tissue as efficiently as smaller molecules [18]. Therefore, smaller antibody fragments and genetically-engineered antibody derivatives have been investigated as drug carriers (see Figure 11.5). These carrier molecules will be discussed in Section 11.8.1. 

A possible way to improve differentiation between normal and diseased tissues is the use of non-specific contrast agents which achieve contrast enhancement based on morphological and physiological properties of tumour tissue. Contrast agents for X-ray, CT and MRI are preferentially taken up by tumour tissue shortly after intravenous injection due to increased tumour vasculature, leaky endothelial structures and enlarged extracellular volumes [34], a phenomenon that is in principle exploitable for optical contrast agents. 

A few examples to render tetrapyrrolic compounds less phototoxic can be found in the hterature. In one approach, carotenoid structures were employed for the synthesis of some carotenoporphyrin derivatives [92-94]. Figure 8 shows two stuctures by way of example. Due to similar photophysical properties of the two structural components, the excited triplet state of the porphyrin is quenched by the carotenoid moiety, thus inhibiting the formation of singlet oxygen, while its fluorescence capabilities are still preserved. Biodistribution studies revealed enhanced uptake into tumour tissue [39,93,95]. However, microscopy studies have shown that such compounds are associated with connective tissues in the tumors rather than with cancerous cells indicating low specificities for mahgnant transformation [96]. 

In the brain, S100A6 is restricted to some subpopulations of neurons and astrocytes (Yamashita et al., 1999). Interestingly, S100A6 is overexpressed in astrocytes associated with the neurodegenerative lesions of amyotrophic lateral sclerosis (ALS) (Hoyaux et al., 2002) as well as in patients with Alzheimer s disease (AD), and in two different AD mouse models (Boom et al., 2004). A deregulation of S100A6 expression was also found in certain tumour tissues (Stulik et al., 2000 Luu et al., 2005 Hancq et al., 2004b Cross et al., 2005) and in patients with acute myeloid leukemia (Murphy et al., 1988). 

For the patient this means a prior injection of a non-radioactive compound containing the stable 10B isotope which accumulates selectively in tumour tissue. In a second step, the person is exposed to low-energy neutrons which destroy the tumour as described above. 

In this review efflux pump inhibitors are classified into two groups low molecular mass inhibitors and polymeric inhibitors, because the high molecular mass of the polymeric excipients prevents absorption into systemic circulation after oral administration. In some cases, just a local inhibition of efflux transporters in the intestine is desired, whereas in other cases also an additional systemic modulation of efflux pumps can be of advantage. For chronical treatments, impact on the complex systemic efflux transporter system can result in severe complications. In this case, an enhanced intestinal absorption of efflux pump substrates can be achieved by using drug delivery systems based on polymeric inhibitors. On the other hand, in cancer therapy it would be of advantage to reduce efflux of anticancer compounds also in the systemic system because tumour tissues often overexpress these transporters. Then a low molecular mass efflux inhibitor could be useful. 

From the earlier work discussed at the 1978 Cold Spring Harbor Meeting on Cell Proliferation there has developed a broad field concerned with the study of growth factors and hormones and their effects on cell growth and differentiation. This area is considered in more detail in Chapter 2 and is of enormous clinical importance for the treatment of cancer. As well as the work on peptide hormones much work has focused on the use of MCF-7 and ZR 75.1 cell lines which were isolated from human breast tumour tissue (Lippman et al., 1977 Engel et al., 1978). These cells respond to oestrogen treatment, but the system is not as simple as first thought and may involve paracrine responses (Leake, 1988). 

HeLa cells (Gey, 1955) were derived originally from tumour tissues and appear to have been transformed in vivo. Although not all neoplastic cell populations will grow indefinitely in vitro many of the human cell lines in common use have such an origin (e.g. HEP2, KB, Detroit 6). 

Other solid particles (S- or Au-colloids, gelatin, targesin, etc.) have similarly been examined for their ability to transfer the 211 At isotope to tumour bearing tissues46,97,99. Application of solid carriers is, however, limited by their lack of biological specificity. Therefore radiocolloids or labelled microspheres are primarily used for local administration into the tumourous tissue itself. 

By encapsulation of the drug in liposomes a favourable alteration of the pharmacokinetics, as well as a lowered toxicity, may be obtained. Even more important is the fact that liposomes collect spontaneously in areas of inflammation and in tumour tissue. This property, which is believed to be due to the inherently leaky vasculature in these areas, has led to the development of several liposomal anti-inflammatory and anticancer agents. 

However, the degree of accumulation of liposomes in tumour tissue depends on their blood circulation time. In order to maximise the accumulation of liposomes, and thus boron, in the tumour, liposomes with long survival time in systemic circulation, should be employed. The liposomal circulation time may be dramatically increased by attachment of long flexible polyethylene glycol (PEG) chains to a proportion of the lipids in the liposomal membrane. Such sterically stabilised liposomes have been shown to circulate for several days, up to a week, without detection by the immune system. 

For successful treatment of cancer by BNCT, it is, however, not enough that the liposomes collect in tumour tissue. For best effect the liposomes should specifically bind to, and be internalised by, the tumour cells. In addition, it is important that the boron-containing compound, after its release from the internalised liposome, is retained within the cell and preferably localises within the cell nucleus. 

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