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Drug Discovery in Cancer Research
During the last two decades of 20th century (1980-2000), there was a significant growth in our knowledge of the molecular mechanism and pathophysiology of human cancers. Many of these mechanisms have been used to suggest targets for development of drugs that have greater antitumour activity with less toxicity to the patient (most cancer drugs have toxic side effects). Encouraging positive clinical results have been obtained through the use of drugs that have been developed using new information at the molecular level. Even today, the major approaches used for treatment of cancer include surgery and radiation that are successful only if the cancer is localized and detected at an early stage.
Some examples of Molecular Targets in Tumour Cells for Cancer Drug Development
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Once the disease has progressed to advanced stage of metastasis, these therapies are less successful. The chemotherapeutic treatments are also largely pallative in these advanced tumours, particularly in case of common epithelial tumours such as lung, colorectal, breast, prostate and pancreatic cancers.
Cancer chemotherapy started in 1940s, when
it was discovered that anticancer activity of nitrogen mustard is due to DNA alkylation, which impairs DNA replication. Many cancer drugs were developed on this principle. Antimetabolite drugs were also developed for cancer treatment. For instance, mithotrexate and mercaptopurine caused pathway alterations-, to which tumour cells were sensitive. A newer medicine cisplatin is used for testicular cancer and gemcitabine (Gemzar) is still used for management of some other cancers.
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Advances in molecular biology also led to the discovery of many genes that affect tumorigenesis and tumour growth through signal transduction, cell cycle regulation, apoptosis, telomere biology and angiogenesis. The problem of drug discovery is to identify the target protein and the corresponding gene which should be used as the basis for drug discovery. Mutation in a gene, such as ras, p53, p16, myc and bir-abl may often be responsible for cancer. In other "ases, overexpression of gene products (e.g. HER EGF, insulin-like growth factor receptors, cyclins, etc.) may also cause cancer. Elevated telomerase activity and increased serum vascular endothelial growth factor (VEGF) are observed in many, if not all cancers, although it may not be the cause, but only a result. In all these cases target validation can be undertaken, using antisense oligoD1'cleotides, ribozymes, antibodies, etc.
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Mousetransgenics/knockouts can also be used. Even if a gene or a protein-protein interaction causing tumor formation is identified, it may not be pharmaceutically tractable. Model peptides have been found and used with low success rate. Success, however, has been achieved using antagonists of specific integrins as antiangiogenesis agents. Antibodies and antisense oligonucleotides can also be used as therapeutic agents. In the signal transduction pathway, Raf and MER were suitable targets, but Ras was not a suitable target. The knowledge that pl6 is an inhibitor of Cdk activity, was used for developing drugs that inhibited Cdks in cancer cells, where defective p16 caused cancer. Yeast genetic screens and DNA chips can also be used identify target proteins in cancer cells
Some mechanism-based cancer therapies in development
| Target |
Drugs |
Estrogen receptor |
Receptor antagonists (reloxifene, Ly353381, Em-800, etc); enzyme inhibitors (ZD-1839, CP-358, CP-358, 774 antibody (C225) |
Integin |
Receptor antagonists (EMD-121974); antibody (vitaxin) |
Protein kinases (Cdks, protein kinase C) and other anzymes |
Kinase inhibitors (CGP-60474, 41251); flavopiridol; FTase inhibitors (R11577, L-778, 123; CP-609, 754); MMPs (Marimastar, AG 3340, BMS-275291, etc) |
Ras, Raf, Bcl2 |
Antisense oligonucleotides (ISIS-2503, 5132; G3139) |
P53 |
Viruses (SCH 58500 Ad-p53, onyx-015) |
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New target based drugs in clinical trials
Several drugs are being developed through identification of the target and some are listed in Table 43.1. Protein kinases are the main targets and small molecule inhibitors (or antibody) of Bcr-abl or EGF receptor are being tried as' future drugs for cancer treatment, Bcr and abl come together in philadelphia chromosome and Bcr-abl gene product has abnormal tyrosine kinase activity. Broad based pharmaceutical efforts have also focussed on developing inhibitors (FTIs, MMP)s) of farnesyltransferase (FTase) and matrix metalloproteinases (MMPs)
SERMs (selective estrogen receptor modulators) are being developed for breast cancer; 5a reductase inhibitors are being developed for prostate cancer and inhibitors of cyclo-oxygenase 2 are being developed for colon cancers.
Breast cancer as a paradigm
Breast cancer is a suitable example, where drug discovery on the basis of molecular mechanism proved successful. These drugs include 0) doxorubicin (Adriamycin) and a texane such as paclitaxel (Toxol) or docetaxel(Toxotere) developed on the basis of their toxicity, (ii) tamoxifen (Nolvadex), developed on the basis of the role of estrogen in breast cancer and (iii) transtuzumab (Herceptin), developed on the basis of the role, of oncogenes. Later it shown that doxorubicin inhibits topoisomerase and texanes (giving 30-40% success) stimulate Tubulin polymerization and tumour apoptosis (via G2/M checkpoint). Other drugs were also developed on the basis of experience with these drugs
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