Cancer has been one of the most prevalent diseases of our time. It has been estimated that more than ten million people developed a malignant tumour and more than 6.5 million people died due to this disease worldwide during the year 2000. In recent years, it has overtaken the heart disease, which is one of the commonest causes of death in some countries like UK.
Many recent advances have taken place in oncology, mainly because of improved understanding of the molecular biology of cancer. Some of the new cancer treatments currently being tested in clinical trials are matrix, metalloproteinase inhibitors, gene therapy and immunotherapy. However, superseding the conventional therapies like chemotherapy and radiation therapy by new cancer treatments based on specific genetic and phenotypic abnormalities in cancer cells still remain a dream.
Natural products
Surgery, radiation therapy and chemotherapy are traditional approaches for the treatment of cancer. Natural products have been the mainstay of cancer chemotherapy for the past 30 years. However, the quickening pace of gene identification and the new technologies of combinatorial chemistry and high throughput screening are expected to provide access to wide range of new drugs.
In reality, natural products are likely to provide many of the lead structures and these will be used as templates for the construction of novel compounds with enhanced biological properties. The American Indians used extracts from the roots of May apple, Podophyllum peltatum as an effective treatment for skin cancers and venereal warts. The main constituent, podophyllotoxin, has been the forerunner of the group of anticancer agents known as the podophyllins, which include the semi-synthetic drugs, etoposide and teneposide. Similarly, the Catharanthus roseus Vinca rosea was used as a hypoglycemic agent in many parts of Asia but in 1958, its main constituents, vinblastin and vincristin were found to have potent cytotoxic properties. Later these agents contributed significantly to the successful treatments of many cancers. These folk medicine discoveries encouraged the National Cancer Institute to begin a large-scale programme for antitumour agents.
The most significant drug to emerge from this massive programme was paclitaxel (taxol) obtained from the bark of the pacific yew trees-Taxus brievifolia. This has provided not only an effective drug but also the springboard for further developments. Camptothecin from the Chinese ornamental tree Camptpotheca acuminata showed promise in the 1970's which was blighted by severe bladder toxicity but chemical manipulation of its structure subsequently produced analogues that include topotecan and ironotecan.
Microorganisms have been the rich source of antibacterial agents but they have also provided some of the key drugs for cancer chemotherapy. Most notable are the bleomycins, dactinomycin, mytomycince, anthracylinones, daunomycin and doxorubicin (adriamycin). All of these were introduced to the clinic before their modes of action had been determined and whereas, most of them damaged DNA through different modes. One of the best examples of a new class of antitumour drugs from a microorganism is the epothinones. After understanding the mechanism of action of a large number of these natural product-based anticancer agents, efforts were directed for microorganism based discovery strategies to develop new cancer drugs.
DNA as a receptor for cancer
It has been well established that the main target of anti tumour drugs, related to their activity is DNA. The modes of interaction of these drugs with this receptor are highly diversified. Based on the nature of their interaction with DNA, these drugs have been classified into three main types of binding - (i) non-intercalating group binding, (ii) intercalation and (iii) covalent bond formation. Different class of compounds possess different modes of interaction and some could exhibit their biological effect through more than one type of interaction. A fourth mode of binding of anti tumour drugs with DNA involves coordination with metal derivatives.
The representative compounds that exhibit non-intercalator group binding are metroxin, distamycin A, lexitropsin, etc. Intercalators comprise of compounds such as anthracyclins (daunomycin, adriamycin), actinomycin, bleomycin, etc. Some of the intercalators comprise of acridines, quinoxaline and delote. The covalent DNA binding agents are pyrrolobenzodiazepines (anthramycins), mytomycins, safromycins and bis-functional alkylating agents. Cisplatin is an example of DNA coordination mode of binding anti tumour drug.
DNA minor groove binders constitute an important of class of derivatives in anticancer therapy. Many research efforts had been aimed at targeting specific sequences in DNA with synthetic ligands with the idea of designing both drugs and molecular probes for DNA polymorphism. Minor groove binders are one of the most widely studied class of agents characterized by high level of sequence specificity and demonstrate to possess several biological activities including therapeutic applications for cancers. This class of compound comprises of antibiotics of natural origin, synthetic, and semi-synthetic compounds of very different type of molecular structure acting with different mechanisms. It is important to underlie that to be effective as an anticancer agent, a minor groove binder needs to covalently and irreversibly bind the DNA with a long permanence of DNA lesion.
In the last two decades, there have been spectacular advances in the understanding of interaction of small non-peptide molecules with DNA. Proteins with sufficient DNA sequence specificity have achieved to a great extent. However, to design and synthesize a non-peptide small molecular weight compound that could bind to a desired DNA sequence of a reasonable size is a challenge to the medicinal chemist. Some of these compounds have undergone clinical studies but none of them has emerged as drugs.
This group at Indian Institute of Chemical Technology became interested and involved in the design and synthesis of sequence selective DNA minor groove binders based on naturally occurring pyrrolobenzodiazepines. These are anti tumour antibiotics that are produced by various Streptomyces species and are generally referred to as the anthramycin family. In this endeavour, some new dimers and hybrids of pyrrolobenzodiazepines have been constructed with the novel structural architecture and evaluated for their DNA binding ability and anticancer potential.
Some of the newly designed and synthesized new molecules are in different stages of pre-clinical studies. This aspect of gene targeting is considered as a promising area of cancer drug discovery for the development of agents that target genes involved in cancer pathogenesis. This investigation will be an attempt to link the sequence specificity of an agent of this type to its anti tumour activity and will use DNA microarray analysis technology to measure gene expression profiles in the tumour cells of patients as a pharmacodynamic end point upon selection of a molecule of this class for clinical study. Attempts are also being made by this group to design prodrugs of this class of molecules that could be delivered at the site of the tumour, i.e. these prodrugs will reach the site and would get activated by certain enzymes that are specific to some type of tumour.
Moreover, this group has also been involved in the development of new DNA topoisomerase-II inhibitors based on naturally occurring lignan, podophyllotoxin as potential anticancer agents. In this context, several new podophyllotoxin congeners have been synthesized and evaluated for their anticancer potential, particularly, to overcome some of the limitations of the therapeutic drug, etoposide and some of the new congeners are undergoing detailed investigations. The investigations have lead to a large number of promising anticancer agents that have been patented as well as published.
Some recent developments in therapies for cancer include signal transduction inhibition- protein kinase inhibitors with broad therapeutic potential. Amongst the target directed drug design, the importance of tyrosine kinase in human cancer is also promising. However, it is apparent the future challenges are great and include improving predictability of preclinical animal models for the development of biomarkers and the design of phase-I trials and overcoming resistance mechanisms, such as, efflux pumps and point mutations. It is observed that the number of anticancer drugs in preclinical and phase-I trials have increased dramatically within the last decade, mainly because of the advent and development of technologies such as sequencing and bioinformatics, expression vectors, three-dimensional structural biology, HTS, combinatorial chemistry and platform approaches to drug discovery. These have resulted in a huge increase in potential drug targets and one can predict an explosion in investigational new drugs in the next coming years.
(The author is with Biotransformation Laboratory, Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad)