**5. Summary**

Throughout history of medicine the process of new drug discovery has been based on natural sources and drugs have been discovered by serendipity (sheer luck) or in a trial-and-error process. While until the mid-1980s new drugs were discovered mainly by serendipity, over the next decade, till mid-1990s, the knowledge of structure was the basis for research, then the starting point was to identify a target and a relationship between structure and function [122]. Nowadays a few major classes of drugs useful in cancer treatment have been defined: (1) General Chemotherapy Drugs (the alkylating agents, anti-neoplastics, anti-metabolites), (2) Steroids, (3) Bisphosphonates, (4) Hormone therapies and (5) Biological therapies/Immuno‐ therapy. This modern classification reflects the fact that anticancer drugs evolved from classical chemotherapeutics discovered mostly by serendipity to drugs acting directly against abnormal proteins in cancer cells designed by rational drug design. All of them have remarkable influence on the growth of cancer cells and on the mechanisms whereby cells replicate, transmit, and translate genetic information.

use in colorectal cancer therapy and Sunitinib discovered by Joseph Schlessinger and Axel Ullrich approved by FDA in 2006 to use for renal cell carcinoma and gastrointestinal stromal tumour. Recent progress in genetic sequencing has led to the discovery of Vemurafenib by Fritz Hoffmann, approved by FDA in 2011. It targets the B-Raf gene that signals the growth of

Recently widespread attention has been given to inhibitors of protein kinases, enzymes that catalyze phosphorylation reactions, a principal mechanism of signal transduction governing various cellular processes including growth, division, migration and apoptosis. Imatinib, developed in the late 1990s by Nicholas Lydon, introduced to clinic by Brian Druker and approved to treat chronic myelogenous leukaemia by FDA in 2001 was the first drug of this new class of small active molecules. It inhibits the oncogene BCR-ABL1 and blocks the signals for cell proliferation, controlling tumour growth. Many imatinib analogues: including Nilotnib, Dasatinib, Bosutinib, Ponatinib, Bafetinib were obtained further by rational drug design. Gefitinib invented by ASTRA/ZENECA (approved by FDA in 2003 but withdrawn in 2005) and Erlotinib invented by OSI (approved by FDA in 2004), were the first selective inhibitors of epidermal growth factor receptor among the kinase inhibitors used for treatment

Monoclonal antibodies that allow the cytotoxin to reach a target required to kill the malignant cells (induce apoptosis), without harming normal cells belong to the unique class of chemo‐ immunotherapeutics. In contrast to small molecule drugs which have a direct impact on their targets, the monoclonal antibodies stimulate the immune system i.e. re-direct targets to the immune system. Most popular includes: Gemtuzumab ozogamicin invented by Wyeth Ayerst and used for the treatment of acute myelogenous leukaemia, but withdrawn from the market in 2010 due to its toxicity, Ibritumomab tiuxetan developed by IDEC Pharmaceuticals used for the treatment of non-Hodgkin's lymphoma, but known to cause serious side effects, Panitu‐ mumab used for the treatment of colon cancer but ineffective, Rituximab developed by IDEC Pharmaceuticals and still used for the treatment of B-cell non-Hodgkin's lymphoma and tositumomab developed by Mark Kaminski and Richard Wahl used for the treatment of non-

Hodgkin's lymphoma (mainly follicular lymphoma), currently in the clinical trials.

limitations, while true cancer treatment is still a challenge for oncology.

Although modern targeted therapies provide a new approach to cancer therapy and similarly to conventional ones are able to suppress tumour growth, but they also have drawbacks and

Throughout history of medicine the process of new drug discovery has been based on natural sources and drugs have been discovered by serendipity (sheer luck) or in a trial-and-error process. While until the mid-1980s new drugs were discovered mainly by serendipity, over the next decade, till mid-1990s, the knowledge of structure was the basis for research, then the starting point was to identify a target and a relationship between structure and function [122]. Nowadays a few major classes of drugs useful in cancer treatment have been defined: (1)

new blood cells in melanoma tumours, which are extremely difficult to treat.

of lung cancer.

62 Drug Discovery

**5. Summary**

Current research are so multidirectional that it is impossible to discuss all of them in a short chapter. New directions in this field include the search for the improved pharmaceutical forms, new analogues of currently used drugs, new chemical compounds (natural or synthetic) of anticancer activity, selective anticancer agents (acting on the basis of pathophysiological mechanisms), the search for drugs among old-known drugs currently used for other indica‐ tions than cancer, search for the methods of precise delivering the anticancer drugs to cancer tissue and stroma or to stimulate the immune system to generate anti-tumor immune responses and protect against cancer.

Even nowadays precursors or generic drugs are frequently discovered by serendipity, while their analogues are developed by purely rational design. Often the newly synthesised drug proved effective in quite different than expected applications. For example Aminoglutethi‐ mide was found to be effective in breast cancer treatment instead of being an antiepileptic, Cisplatin, an electrolysis product, was discovered to be cytotoxic or Tamoxifen antiestrogenic activity of *cis*-isomer was discovered as unexpected bonus in the search for drugs to treat mania in bipolar disorder. Sometimes surprisingly a new field of activity is revealed for a long known drug. For example potassium-sparing diuretic Amiloride is effective in glioma; sedative Thalidomide, linked to birth defects, slows the propagation prostate cancer; Tebrophen, antiviral drug, slows the propagation of breast cancer; S-dimethylarsin-gluthathione, an organic form of arsenic, slow solid tumours expansion; anti-epileptic Valproic and Rapamycin, immunosuppressor in organ transplantation are valuable in antitumor therapy; Gossypol, potential male contraceptive overcome resistance to Cisplatin; antimalarial chloroquine may address a critical cell nutrition issue with proliferating cancer cells while insecticide benzoyl‐ phenylurea helps understand the microtubule assembly process important for growth of the pancreatic cancer cell. Anticancer properties have been ascertained to be shown by aspirin used commonly as analgesic, antipyretic and an anti-inflammatory medication, 9-aminoacri‐ dine used as an antiprotozoa and antibacterial agent and Quinacrine commonly used antima‐ larial drug. The use of long know drugs fasten modern process of drug discovery, which involves the identification of candidates, synthesis, characterization, screening, and assays for therapeutic efficacy and proceeds through many stages including discovery, product charac‐ terisation, formulation, pharmacokinetics, preclinical toxicology testing and IND (Investiga‐ tional New Drug) application, bioanalytical testing and clinical trials. The new drugs (new completely or a long known one) often have many adverse effects. Sometimes in the final step the new drug proves toxic, ineffective or even carcinogenic. Many widely applied chemother‐ apeutic anticancer agents (nitrogen mustards, HN2 and HN3, treatamine, Chlorambucil, Sacrolysin, Melphalan, and Busulphan), have been recognized as a source of secondary cancers and thus classified as definite carcinogens.

**Author details**

**References**

Jolanta Natalia Latosińska\*

and Magdalena Latosińska

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\*Address all correspondence to: jolanta.latosinska@amu.edu.pl

can.iarc.fr, accessed on day/month/year.

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Faculty of Physics, Adam Mickiewicz University, Poznań, Poland

Sometimes known carcinogens have became invaluable drugs widely applied in clinical oncology. The most impressive example is arsenic - a component of the well known Poison of Kings (As2O3). It was used in traditional Chinese medicine in the treatment of promyelocytic leukaemia and acute myelogenous leukaemia. Reaglar containing arsenic was used by Hipocrates as a component of antitumor liniment. Avicenna in the 11th c. recommended it for cancer, both internally and topically. In the 16th century Paracelsus used it as a drug but linked with a cancer disease. In 1786 Thomas Fowler discovered Fowler's Solution (a 1% aqueous solution of potassium arsenite, KAsO2),which was applied as first chemotherapeutic in chronic myeloid leukaemia treatment in 1865 by Lissauer and persisted till the introduction of the first modern cytotoxic drugs in the 1940s. In 1931, its use in chronic myeloid leukaemia was described. In the late 1960s in China, an arsenic containing liniment was rediscovered for use as an effective anticancer treatment in melanoma. First reports of the intravenous administra‐ tion of Fowler's Solution in acute promyelocytic leukaemia appeared in the 1990s, also in China. But in the 1990s IARC classified arsenic compounds as definite carcinogens. Despite this, in 2001 Fowler's Solution was accepted by FDA for the treatment of relapsed or refractory acute promyelocytic leukaemia in children. After being abandoned for decades, arsenic trioxide in the 21st c started to be prescribed as a drug for acute promyelocytic leukaemia, and still it is classified as definite anticancer. Recently some hope rises with realgar as well as new arsenic-based compounds (e.g. C-glycosides), which have been intensively studied. On the other hand, a very recent studies performed by Peter S. Nelson et al. indicated that chemo‐ therapy can damage healthy cells which secrete a protein WNT16B that sustains tumour growth and results in a resistance to further treatment [123]. This proves that chemotherapy itself can boost cancer growth. The paradox drug/carciogen concerns not only chemothera‐ peutics but also the methods, which revolutionized the treatment of cancer, being on the other hand carcinogenic, like X-Ray widely used in the diagnosis of cancer cells, cancer treatment and anticancer drug design, UV radiation being a basis of the photodynamic therapy. Para‐ celsus, father of toxicology already wrote "*All substances are poisons: there is none which is not a poison. The right dose differentiates a poison and a remedy.*" Paraphrasing him - the method and conditions of the use differentiates a carcinogen and anticancer drug. Thus the search for new drugs among carcinogens seems quite reasonable, while the protection against contact with or exposure to a carcinogen is a necessity.

The recent advances in genomics and proteomics deliver a promise of understanding the true internal mechanisms of cancerogenesis - a basis for cancer diseases. They cover the knowledge of genes alteration caused by cancer, its influence on the proteins encoded by them, the interaction of these proteins with each other in living cells, the resulting changes in the specific tissues and finally the effect on the entire body. The achievements in this field delimit new fully rational directions in anticancer drug discovery and development of drugs addressing the specific needs (targeted drugs).
