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|Year : 2012 | Volume
| Issue : 1 | Page : 63-67
Development of botanical principles for clinical use in cancer: Where are we lacking?
RJ Poojari, AG Patil, VS Gota
Department of Clinical Pharmacology, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai, India
|Date of Submission||02-May-2011|
|Date of Decision||08-Sep-2011|
|Date of Acceptance||24-Oct-2011|
|Date of Web Publication||25-Feb-2012|
R J Poojari
Department of Clinical Pharmacology, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai
Source of Support: None, Conflict of Interest: None
Development of drugs from plant sources (botanicals) for the treatment of cancer has not been successful in India, despite a plethora of medicinal plants and an equal number of experiments demonstrating anti-cancer activity of plant principles in vitro. There are several pitfalls in our approach to botanical drug development. Foremost is the lack of industry-academia collaborations in this field. Research goals in Indian academic institutions are generally short-term and mostly aimed at fulfilling the minimum requirements of a doctoral/MD or MPharm thesis. Secondly, quality assurance of herbal formulations is difficult to achieve and good manufacturing practices are expensive to implement. This could introduce bias during the biological evaluation of botanicals. A systematic approach covering a wide range of investigations including but not limited to mechanistic studies, potential herb-drug interactions, pharmacokinetics and bioavailability could help in the optimization of herbal formulations in the preclinical stage of development before they can be considered for clinical trials. Government initiatives such as Ayurveda, Unani, Siddha and Homeopathic have encouraged research in these areas, but are insufficient to promote focused and aggressive evaluation of potential herbs. Particular emphasis should be given to clinical pharmacokinetics, drug interactions and clinical trials in specific cancers for the evaluation of dosage, safety, efficacy and concomitant use with chemotherapy. Only such policies can result in meaningful evaluation of botanicals for cancer therapy.
Keywords: Botanical medicines, cancer, clinical trials
|How to cite this article:|
Poojari R J, Patil A G, Gota V S. Development of botanical principles for clinical use in cancer: Where are we lacking?. J Postgrad Med 2012;58:63-7
|How to cite this URL:|
Poojari R J, Patil A G, Gota V S. Development of botanical principles for clinical use in cancer: Where are we lacking?. J Postgrad Med [serial online] 2012 [cited 2021 Mar 2];58:63-7. Available from: https://www.jpgmonline.com/text.asp?2012/58/1/63/93257
| :: Introduction|| |
India is a goldmine of well-recorded and well-practiced knowledge of traditional herbal medicine. A quarter of all medicinal formulations contain at least one component derived from plants or plant-derived synthetic analogs. According to the World Health Organization (WHO), 80% of the world's population, primarily in developing countries relies on plant-derived medicines for their healthcare. Plants, especially with ethnopharmacological uses have been the primary sources of medicines for early drug discovery. Current drug discovery from plants has mainly relied on bioactivity-guided isolation of active principles which led to the discovery of anticancer drugs like Camptothecin, Paclitaxel, Epipodophyllotoxin, Vinblastine, Vincristine and Venorelbine. Several new derivatives of known anticancer agents are undergoing clinical trials.  Many plant-derived (botanicals) chemopreventive agents have been shown to suppress cancer cell proliferation, inhibit growth factor signaling pathways, induce apoptosis, inhibit NF-κB, AP-1 and JAK-STAT activation pathways, inhibit angiogenesis, suppress the expression of anti-apoptotic proteins, and inhibit COX-2 which can act as adjuncts to current cancer therapies. , But no systematic effort has been made for the further development of these agents. Not many botanicals have faced the rigorous test of randomized controlled trials in cancer. Some of the leading plant-derived compounds which have entered clinical trials for specific cancers are shown in [Table 1]. This paper highlights the pitfalls in the development of botanical medicines for clinical use in cancer in India.
| :: Key Issues|| |
Research in academic institutions
So where does the problem lie? The problem is that scientific research, including research work done for graduate, MD, PhD thesis or even post-doctoral work remains stagnant. Most of the research is carried out as part of a dissertation leading to a degree but is not further followed up to its logical conclusion. Poor research infrastructure and poor quality of research in many Indian Universities often limits in-depth evaluation of initial leads. Methodological deficiencies often result in evidence that is not convincing enough, although it may still get published in peer-reviewed journals. The most common course in the development of an investigational botanical is: i) to show effectiveness in in vitro screening and in vivo models of cancer, ii) to conduct toxicity and pharmacokinetic studies and iii) to study the mechanisms of action. Although the first two steps are easily achieved, identifying the target and evaluating the mechanism of action poses significant problems. Botanicals are generally a mixture of several constituents and converging on a single component responsible for biological activity is difficult. Quite often, more than one constituent contributes to the overall activity of the mixture. Development of botanicals beyond this stage requires industry-academia collaborations. Such collaborations are not easily established and even if established are difficult to sustain. Involvement of Small and Medium-Sized Enterprises in indigenous drug development has not caught up in India as it has in the West.
Research methodology and focus
Clinical development is hampered by the lack of adequate or accepted research methodology for evaluating traditional medicine. The quantity and quality of the safety and efficacy data on traditional medicine are far from sufficient to meet the criteria needed to support their widespread clinical use.  The basic tenets of cancer therapy would be applicable to botanicals also and hence they are less likely to be successful as standalone treatments. Therefore efforts should be made to evaluate these drugs in combination with other anticancer drugs, specifically looking at synergism or chemoprotective actions. Research should also focus on the systematic evaluation of chemopreventive or anticancer effects through cutting-edge high-throughput screening (HTS) tools or by using validated biomarkers. A plethora of prognostic, predictive and imaging biomarkers have been validated which could be used as surrogates in preclinical models as well as clinical trials to obtain early leads about the effectiveness of a botanical principle.
Question of quality
Quality is an important attribute of a product for its acceptability to consumers and regulatory authorities. The source of a herb is the deciding factor in the overall quality of the botanical product. Several factors including geographical locations, climatic conditions, environmental hazards, use of insecticides, harvesting methods and collection protocols may contribute to inconsistency of herbs making it difficult to standardize the quality of the end product. Lack of pharmacopoeia standards for each herb also makes it difficult to have quality control (QC) standards to ascertain drug purity. Apprehensions about microbial contamination and presence of heavy metals should be addressed adequately. Inconsistencies in the quality will impact research. For instance, safety and efficacy assessments in preclinical and clinical phases of development could be seriously undermined if the supplier is unable to keep batch to batch variability in the composition within acceptable limits.
Botanical principles in general have poor oral bioavailability which requires special formulations to overcome the 'intestinal barrier'. Not many researchers are keen to overcome this stumbling block and the focus will shift towards the 'next exciting herb'. With the exception of Curcumin in recent years one cannot recollect any other principle being a subject of intensive research to crack the bioavailability enigma.
How do we overcome challenges in the development of botanical drugs for cancer?
- Herbal anticancer drug research is not a target-centric approach. The drug discovery and development process does not go through the usual process of target identification, validation, lead identification and optimization but follows a 'reverse pharmacology' path [Figure 1]a and b. Herbal drug extracts require a great deal of optimization because a combination of different components is often associated with better biological activity rather than a highly purified extract. There is a need to adopt a systematic approach for the assessment of botanicals for their utility in the treatment of cancer as illustrated in [Figure 2].
|Figure 1: (a) Drug discovery and development process; (b) Reverse pharmacology approach in herbal drug research|
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- Optimizing formulations requires a series of pharmacokinetic studies for each route of administration. For instance, one of the major obstacles in the clinical development of Curcumin is its poor oral bioavailability. Several formulations including nanocurcumin and Solid Lipid Curcumin Particle have been developed and evaluated in clinical trials.  These efforts have paid rich dividends with each novel formulation demonstrating better bioavailability of Curcumin. Participation of industry in these achievements is crucial to take the initial breakthroughs provided by academic researchers forward.
- Most herbal formulations consist of a combination of herbal principles. There is a potential for botanical- drug interactions. As a result, the effectiveness of one may increase or decrease in the body. For example, many products including Aloe vera, Guggul, Ginkgo biloba, Ginseng and Green tea are known to interact with conventional chemotherapeutic drugs leading to serious adverse reactions.  Pharmacokinetic-pharmacodynamic (PK-PD) studies, toxicological studies, toxicokinetic assessments should be conducted systematically in preclinical model systems in combination with chemotherapeutic drugs to gather more data about the interactions. Methodologically sound studies that could evaluate such interactions should also be designed and conducted with the help of qualified clinical pharmacologists so that interactions if any are identified early in the process of clinical development of the botanical agent.
- Good Manufacturing Practice (GMP) and quality control norms should be adopted to minimize the batch-to-batch variation in herbal products containing complex mixtures of many herb components. Stringent QC, quality assurance (QA), good laboratory practices (GLP), GMP practices and thorough phytochemical testing is essential to enforce safety, identity, strength, purity and quality in products.  The high cost involved in GMP practices is a deterrent for many companies to invest heavily in the untested territory of botanical drugs. The government should encourage research in this area through grants and marketing exclusivity.
- Clinical trials for cancer are already underway with Curcumin, Resveratrol, and Green tea. There is a need to evaluate herbal medicine for specific cancers in terms of dosage, efficacy, safety and concomitant use with chemotherapy. More randomized controlled trials are needed to generate unequivocal and unbiased evidence. Perhaps the best way to exploit botanicals in cancer therapy is to use them in the adjuvant setting alongside current best practice, with an aim to prevent recurrence, and clinical trials should be designed to answer such questions. Most clinical trial approaches for botanicals in cancer have been small, had problems with research designs, lacked appropriate control groups, or had issues that affected meaningful interpretation of data. , Therefore, scientific evidence for the effectiveness of herbal medicines in cancer is short of widespread acceptability and more rigorous research is needed.
Several schemes have been launched by Government of India for promoting Ayurveda, Unani, Siddha and Homeopathic (AYUSH) Systems of Medicine. These schemes are: i) Extra Mural Research project scheme of AYUSH, including the accreditation of organizations for research and development (R and D) in the field of AYUSH under Ministry of Health and Family Welfare, ii) Golden Triangle Partnership scheme between AYUSH, Council of Scientific and Industrial Research (CSIR) and Indian Council of Medical Research, iii) National Medicinal Plants Board, iv) Traditional Knowledge Digital Library (TKDL) - a potent tool to prevent grant of wrong patents v) New Millennium Indian Technology Leadership Initiative launched by CSIR to attain a global leadership position in a "Team India Spirit'' for Indian Industry - institutional alliances on the modern system of medicine, vi) Technology Development Board and vii) Drugs and Pharmaceuticals Research Program (DPRP) of Department of Science and Technology managed by Drug Development Promotion Board and Expert Committee on DPRP. 
The vision of these agencies and schemes is: i) Synergize the strength of R and D institutions, academia and the Indian pharmaceutical industry for discovery and introduction of new drugs, ii) Capacity Building (state-of-the-art facilities and HRD), iii) Promote herbal agents with therapeutic potential in cancer (AYUSH in particular), iv) Set up national facilities on pharma informatics, standardization and quality control, v) Strengthen pharma R and D in the field of oncology with respect to botanical medicines and vi) Combine the TKDL with the International Patent System through an International Traditional Knowledge Resource Classification System (ITKRCS) which is likely to facilitate greater awareness on the traditional knowledge systems by leveraging the modern system of dissemination i.e. Information Technology, in particular, the Internet and Web technologies. It is anticipated that the TKRC structure and details will create interest in those countries that are concerned about prevention of grant of wrong patents for non-original discoveries relating to traditional knowledge systems. Sadly, these initiatives have not yielded the desired results and our cupboards are still bare with nothing to show in terms of an indigenous drug for any cancer. The agencies should curb their natural tendency to fund small projects with questionable scientific merits. Instead, a panel comprising key opinion leaders (KOLs) should identify indigenous problems and invite proposals from select labs with the necessary knowhow, with provision for a large funding. These steps will discourage frivolous research, ensure optimal utilization of available funds and allow focused investigations in herbal drug development at the same time.
| :: Conclusion and Future Prospects|| |
In conclusion, there is preliminary evidence for possible application of some herbal preparations in cancer. However, the clinical efficacy of none of the herbal medicines has so far been demonstrated beyond doubt. Newer approaches utilizing innovative formulations, HTS, combinatorial chemistry, biomarkers, translational research tools and bioinformatics can yield rich dividends in the near future. Academia-industry collaborations and pertinent government initiatives are crucial for continued interest in botanical drug discovery. Furthermore, large-scale, well-designed clinical trials in cancer are required to provide more conclusive proof of their efficacy.
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