Principales características de la Central de Alarmas

Anti-EGFr monoclonal antibodies block ligand binding, and inhibit the growth of human cancer cells stimulated by EGF or TGFa in culture and as xenografts in nude mice (Masui et al., 1984, Ennis et al., 1989, Mendelsohn, 1988, 1990a,b). Cellular toxins have been linked with anti-EGFr antibodies (Ozawa et al., 1989) and with EGF or TGFa (Chaudhary et al., 1987) achieving useful tumour killing of human tum our xenografts without excessive normal tissue toxicity (Heimbrook et al., 1990).

2) EGF

EGF inhibits the growth of cultured human cancer cells with high levels of EGFr (greater than 10® EGFr/cell) e.g. A431 human vulval epidermoid cancer (Kawamoto et al., 1984), human breast cancer M C F-7/AdrR (Vickers et al., 1988) and MDA-468 (Filmus et al..

1985). The response to EGF is influenced by the number of EGFr and the dose of EGF. In cells with low levels of EGFr, growth is

stimulated by an optimal nanomolar concentration of EGF with little effect at higher doses. When an optimal EGFr number is exceeded, nanomolar concentrations of EGF inhibit growth and stimulation occurs with picomolar concentrations of EGF.

Growth inhibition in MDA-468 cells by EGF appears to be partly mediated by glucose deficiency and cellular starvation (Kaplan et al., 1990b) due to stimulation of glucose consumption (Diamond et al., 1978, Conricode and Ochs, 1990). Cells are arrested at the G 1/S boundary of the cell cycle (Prasad and Church, 1991).

EGF enhances cytotoxicity of different classes of cytotoxic drugs (adriamycin, mitomycin C, cyclophosphamide, 5-fluorouracil and cisplatin) in a range of human xenografts with varying EGFr

expression (Amagase et al., 1989). Modulation of chemosensitivity to 5-fluorouracil and cisplatin appears to be directly related to the level of EGFr expression. EGF may alter drug sensitivity via protein kinase C, as the development of multidrug drug resistance in human and rodent cell lines is associated with increased

activity of protein kinase C (Posada et al., 1989) and EGFr (Meyers et al., 1986,1988) in comparison with the parent line. This is supported by the observation that inhibition of protein kinase C by staurosporine partially reverses adriamycin resistance in a

multidrug resistant human and murine cell line (Posada et al., 1989).

EGF alone or in combination with chemotherapy may provide an alternate approach for targetting the EGFr for therapy. Normal cells including bone marrow and intestinal epithelium express low levels of EGFr (less than 10^ EGFr/cell) (Forgue-Lafitte et al., 1980, Amagase et al., 1989), and, therefore, a therapeutic window may be gained with high doses of EGF for tumours expressing high levels of EGFr. Tumour cells may also differ from normal cells for ligand uptake, processing and receptor down regulation (Harris, 1990). Tumour cells may be more dependent on EGFr signalling pathways for proliferation, whereas EGF is also involved in differentiation in normal cells (Snedeker et al., 1991).

1.3.3 PROTEIN KINASE C

Protein kinase C plays a central role in signal transduction by a variety of growth factors controlling cellular proliferation and is, therefore, one of the key targets for therapy (Tritton and

Hickman, 1990). Modulation of protein kinase C activity can be achieved by both activation and inhibition (Tritton and Hickman, 1990). Calphostin C inhibits protein kinase C and is cytotoxic for P388 leukaemia in culture and in vivo (Tritton and Hickman, 1990). Bryostatin is a potent activator of protein kinase C and has

antineoplastic activity in screening systems (Pettit et al., 1982). Selectivity against cancer cells is possible due to upregulation of signalling pathways (Powis et al, 1990).

1.3.4 DRUG RESISTANCE

3 ip MRS has a potential role in monitoring the activity of agents modifying tumour biology with the aim of enhancing

c h e m o s e n s itiv ity .

The induction of MDR is associated with enhanced drug efflux by the ATP dependent P-glycoprotein pump located in the plasma membrane (Deuchars and Ling, 1989). Chemosensitivity can be modulated by a large range of agents which compete for the drug binding sites on P-glycoprotein e.g. verapamil, quinidine, tamoxifen (Kaye, 1988). Some of these have entered clinical trials.

Agents inhibiting ATP production may also have a role in

therapeutic modulation of MDR as the membrane pump is driven by ATP. 3 ip MRS of the multidrug resistant human breast cancer cells, M C F-7/AdrR has shown that cellular ATP is reduced by 2-

deoxyglucose (Kaplan et al., 1991). ATP production can also be compromised by lonidamine (Rosbe et al., 1989), hypoxia (Freyer et al.,1992) and EGF (Kaplan et al., 1990) and all these may have a role in therapeutic modulation.

1.3.5 HYPOXIA

There is substantial evidence for the presence of hypoxia in both experimental tumour models and in human tumours (for review see: Vaupel et al., 1989, Stratford, 1992). Variations in oxygen levels in human breast cancer has been measured with microelectrodes

(Vaupel et a l.,1991). It is clear that hypoxia causes resistance to ionising radiation (Gray et al., 1953, Hall and Bedford, 1966) and

that it may limit the success of radiotherapy for certain human tumours (Bush et al., 1978, Gatenby et al., 1988, Overgaard et al.,

1986). The response to some anticancer drugs can also be modified by hypoxia (supra vide) and, therefore, manipulation of the

oxygenation status of tumours may be of therapeutic advantage. 3 ip MRS can detect changes in tum our bioenergetics following physiological manipulation of blood flow in experimental tumours (Bremner et al., 1991, Burney et al., 1991, Wood et al., 1991) and, therefore, offers the potential for selecting tumours fo r this form of therapy. However, the induction of radiobiological hypoxia by a range of treatments (clamping, hydralazine, tum our necrosis factor and BW12C79), is not always accompanied by a change in the 3 ip MR spectrum (Stratford et al., 1992). The pattern of the vascular architecture and consequently the supply of nutrients, as well as the preferred pathway for ATP production are likely to be

important factors influencing the 3 ip MR spectrum.

1.3.6 HYPOXIA AND DRUG ACTIVATION

Cellular oxygenation can influence the response to anti-cancer drugs by an effect on drug activation.