Tumour solid

The antisense oligonucleotide LErafAON against the serine/threonine kinase c-Raf has been tested in phase I clinical trials. The antisense oligonucleotides ISIS-5132, which also inhibits c-Raf, and ISIS-3521, which inhibits PKC, went through different phase clinical trials with solid tumour patients. Unfortunately, no objective responses occurred with these PKI. GEM-231, an oligonucleotide targeting the RIa subunit of protein kinase A is currently undergoing phase I/II clinical trials alone or in combination with traditional therapy for the treatment of solid cancers [3]. 

Despite the scientific elegance of the antibody-mediated approach to tumour detection/destruc-tion, initial clinical trials proved disappointing. A number of factors contributed to their poor therapeutic performance, particularly against solid tumours. Most such factors relate directly/ indirectly to the fact that the first generation of such drugs utilized whole monoclonal antibody preparations of murine origin. These factors include ... 

GM-CSF is undetectable in the serum of normal humans, and no normal cells have been shown to express this protein constitutively. Some transformed cells may constitutively express GM-CSF, and it is actively synthesised and secreted by antigen- and lectin-stimulated T cells and by endothelial cells and fibroblasts exposed to TNF, IL-1 or endotoxin. Other sources of GM-CSF include stimulated B lymphocytes, macrophages, mast cells and osteoblasts, whilst TNF and IL-1 can stimulate its production by acute myeloid leukaemia cells. Some solid tumours and synovial cells from rheumatoid joints may also express GM-CSF and this may be important in disease pathology. 

Neutropenias may also arise as a side effect or deliberate consequence of therapy. For example, some drugs used in the treatment of inflammatory disorders are immunosuppressive, and if these decrease the number of circulating neutrophils to below the critical threshold level, then susceptibility to infection may result. During chemotherapy for the treatment of solid tumours, an inevitable consequence of cytotoxic therapy is that the bone marrow will be destroyed by the drugs thus, patients will have a considerable risk of infection during this induction period. Similarly, during the treatment of haematological disorders (e.g. leukemias and myelodysplastic syndromes), the aim of therapy is to attack the bone marrow so as to destroy... 

Bourgeois H, Vermorken J, Dark G, Jones A, Fumoleau P, Stupp R, Tourani J, Brain E, Nguyen L, Lefresne F, Puozzo C (2007) Evaluation of oral versus intravenous dose of vinorelbine to achieve equivalent blood exposures in patients with solid tumours. Cancer Chemotherapy and Pharmacology 60 407 113. 

The most widely used drug in this category is cisplatin. Therfeore, we have summarized below its action at the chromatin level. The anti-tumour drug cis-diamminedichloroplatinum(II) (cisplatin) is employed for the treatment of ovarian and testicular carcinomas, as well as solid tumours (Loehrer and Einhorn, 1984 Zamble and Lippard 1995). 

Table 2. CBP, p300 and p/CAF mutations found solid tumours ...

Androulakis N, Kouroussis C, Mavroudis D, et al. Phase I study of weekly pacli-taxel and liposomal doxorubicin in patients with advanced solid tumours. Eur J Cancer 2002 38 1992. 

Bos AM, de Vries EC( Dombemovsky P, Aamdal S, Uges DR, Schrijvers D, Wanders J, Roelvink MW, Hanauske AR, Bortini S, Capriati A, Crea AE, Vermorken JB. (2001) Pharmacokinetics of MEN-10755, a novel anthracycline disaccharide analogue, in two phase I studies in adults with advanced solid tumours. Cancer Chemother Pharmacol 48 361-369. 

It has been hypothesized that folate receptor-mediated endocytosis can be exploited for the selective delivery of drugs by covalent attachment to folate via its y-carboxyl group. This concept was primarily designed for the targeting of various biomolecules to solid tumours. For a... 

The success of treating tumours, especially solid tumours, by systemic therapy depends on various characteristics of the tumour. Besides the importance of intrinsic drug activity and the potential targets within the tumour cells, drug pharmacokinetics and whole body distribution, site of delivery and the ability of site-specific targeting (affinity) are important features. 

In summary, in solid tumours the laws of hydrodynamics and transport of solutes mitigate against the successful delivery of drugs and macromolecules to tumour cells. 

Biophysical properties such as high thermal stability are thus of paramount importance in the decision as to whether or not these molecules are useful in vivo. The above described approaches may provide a strategy to meet these requirements and may eventually result in attractive modalities for the targeting of solid tumours in patients. 

For a review on optimizing liposomes for delivery of chemotherapeutic agents to solid tumours, readers are referred to Drummond et al. [113]. 

Blood vessels Endothelia Tumour vasculature Lactoferrin, OxLDL Anti-VEGF-R Ab, VEGF Rat Atherosclerosis Solid tumours... 

The reason for the selective toxicity of 6-mercaptopuiine remains to be established, but two factors may be of primary importance. 6-Mercaptopurine is anabolized primarily, if not exclusively, to the monophosphate level, and it is readily catabolized by xanthine oxidase, an enzyme that is low in most cancer cells compared to normal cells. Another factor that must be considered is the metabolic state of the target cells. Actively proliferating leukaemia cells are more sensitive to 6-mercaptopurine, as they are to all antimetabolites, than cells in the so-called Gq or stationary phase. Although this does not explain the difference between 6-mercaptopurine and other purine analogues, it may explain the ineffectiveness of 6-mercaptopurine against solid tumours, most of the cells of which are in the non-dividing state. 

Hall MD, Martin C, Eerguson DJP, et al. Comparative efficacy of novel platinum(IV) compotmds with established chemotherapeutic drugs in solid tumour models. Biochem Pharmacol 2004 67 17-30. 

Collier LS, Carlson CM, Ravimohan S et al (2005) Cancer gene discovery in solid tumours using transposon-based somatic mutagenesis in the mouse. Nature 436 272-276... 

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