Reducing the side-effects of chemotherapy Medicinal chemist and cancer researcher Dr JiaJiu Shaw discusses the need to develop novel DR JIAJIU SHAW chemoprotective agents, and shares the details of his own work towards accomplishing this goal which is known to be associated with several the elevated levels of TNF-α and TGF-β. This is potential side-effects. This is why we did not another promising area we may pursue. conduct many chemoprotective studies on UTL-4 compounds. One of the main reasons Do you have any results from the SBIR phase we pursued UTL-5g as a chemoprotector is that II study? most of the UTL-5 compounds are associated with very low acute toxicity and UTL-5g shows In addition to further confirming that UTL-5g the highest potency among them. reduces the side-effects induced by cisplatin, we have investigated the metabolic behaviour of What are the benefits of taking a UTL-5g, ultimately finding that it is dramatically collaborative approach to your project? In different from a structurally similar drug, particular, how did your collaborations with leflunomide. I believe this difference is one Drs Frederick Valeriote and Ben Chen help of the main reasons that UTL-5g has a lower move your study in the right direction? acute toxicity than leflunomide. This was a significant finding and it formed the basis of Dr Valeriote has more than 35 years of a published review paper. Another important experience in cancer research. He also finding originated from the repeat dose toxicity has extensive research experience in study, in which we treated mice with up to radioprotection, which is another potential 1,500 mg/kg per day orally for seven days; there Could you introduce your current research application of UTL-5g. Dr Chen has over 30 were no treatment-related deaths and only project entitled ‘Novel small-molecule TNF years of research experience in immunology minimal, non-limiting toxicological effects on modulators as chemoprotective agents’? and haematology; both are related areas clinical signs and clinical pathology endpoints. What are its chief aims and mission? of chemoprotection and radioprotection. Histopathology revealed that the spleen was Their collaborative efforts are critical to my a target organ. Microscopically, increased In this project, we aim to show that UTL-5g continued productive research progress. Of haematopoiesis of the spleen was seen in all protects tissues from chemotherapy-induced course, there are also many other collaborators UTL-5g treatment groups, which is consistent side-effects. We started by examining the and supporters that I have to be thankful for, with the platelet protection effect of UTL-5g. protective effects of UTL-5g on nephrotoxicity, including Drs Stephen Brown, An-Rong Lee and hepatotoxicity and myelotoxicity on cisplatin. Wen-Hsin Huang. You have been working on your current With the current successful data, we are project since 2009 and it is due for beginning to expand our research to investigate Will there be any wider benefits to the completion this summer. What is the next whether UTL-5g protects tissues against development of UTL-5g? step after SBIR phase II? oxaliplatin. We may even examine additional anticancer therapeutics. Yes, as I mentioned briefly, UTL-5g shows We’ll carefully review the overall data and promising chemoprotective properties against decide whether it makes sense to add more Your project focuses on the tumour cisplatin-induced side-effects. Meanwhile, we studies and file an investigational new drug necrosis factor alpha (TNF-α) inhibitor, are also evaluating the chemoprotective effect of application for chemoprotection. We may UTL-5g. Why was UTL-4 unacceptable as a UTL-5g against oxaliplatin – as it is more widely also consider the possibility of using it as a chemoprotective agent? prescribed today – with the support of a newly- radioprotector. Furthermore, we now have new issued Small Business Innovation Research compounds – based on the UTL-5 platform – in UTL-4 compounds are the predecessors of UTL-5 (SBIR) phase I grant. The other application is its the pipeline under preclinical development. If compounds. Although UTL-4 compounds display radioprotective effect. Under a phase I contract the new compounds are significantly better significant anti-inflammatory properties, their of the SBIR programme, we showed that UTL-5g than UTL-5g, we may have a tough decision as IC50 values are similar to that of leflunomide, could protect an irradiated lung by lowering to what to do next. 16 INTERNATIONAL INNOVATION DR JIAJIU SHAW Protection perfection Researchers at US drug discovery company 21st Century Therapeutics, Inc. may hold the key to advancing chemoprotection, potentially enabling clinicians to negate the side-effects of chemotherapy MEDICAL SCIENCE HAS already seen a bone marrow as well, reducing the production of vomiting, hypotension and, in some cases, number of breakthroughs in the field of cancer platelets and white blood cells. Finally, and most cutaneous reactions – as well as being relatively treatment, and pre-eminent among these has importantly, hepatotoxicity is induced in high inconvenient to administer (by intravenous been the discovery of platinum-based anticancer doses, limiting the amount of cisplatin that can infusion). A novel chemoprotector for use with drugs. The first cisplatin, was approved by the be used at any given time. cisplatin would therefore be an extremely useful US Food and Drug Administration (FDA) for clinical tool, and the development of such an clinical use in the US in 1978 – and its efficacy agent is the current goal of Dr JiaJiu Shaw’s CHEMOPROTECTION is such that it remains a popular component research group at 21st Century Therapeutics, in combination chemotherapies today. At the The side-effects of chemotherapy, and Inc., a small drug discovery company based in time, its discovery revolutionised the treatment platinum-based chemotherapy in particular, Michigan, USA. Their efforts have been focused of this persistent and multifarious disease. limit an otherwise very effective treatment. on the tumour necrosis factor alpha (TNF-α) Although particularly effective against testicular Much attention has therefore been devoted modulator UTL-5g. This drug candidate, selected cancer, its introduction saw cure rates for most to the development of chemoprotective from their own small-molecule library, has other forms of cancer improve significantly. agents to nullify them. As it stands, the FDA already brought forth some promising results. has approved only one adjuvant to cisplatin There was, however, a price to be paid for for this purpose: amifostine, marketed under LEAVING THE COMPETITION BEHIND cisplatin’s success – and more than 30 years the trade name Ethyol. The use of this drug is later, the physical cost of effective chemotherapy becoming increasingly widespread, but when Having secured funding from the National still lingers on in patients receiving treatment. administered in conjunction with cisplatin it Institutes of Health (NIH) for a Small Business Platinum-based chemotherapeutic agents target remains controversial. The main problem is that Innovation Research (SBIR) phase I trial of rapidly dividing cells, curbing tumour growth the two substances are not pharmacologically UTL-5g, Shaw and his collaborators had the but also leading to hair loss and damage to the compatible, which may cause Ethyol to have a opportunity to investigate the potential of skin and nails. Cisplatin adds fresh toxicities of tumour-protective effect. their candidate against Ethyol. UTL-5g was the its own. With repeated doses, damage to the ideal subject for further testing because it is a kidney cells evolves slowly but predictably, and Ethyol is also associated with side-effects patented TNF-α modulator functional in vivo, in 25-30 per cent of cases the drug will affect the of its own – including dizziness, nausea, and is easily synthesisable via a simple one- WWW.RESEARCHMEDIA.EU 17 INTELLIGENCE batch, two-step reaction from readily available this new phase of study, the group obtained starting materials. The SBIR phase I trial involved further proof of UTL-5g’s chemoprotective NOVEL SMALL-MOLECULE numerous animal studies, and the findings were effects, as well as examining the mechanisms TNF- MODULATORS AS α overwhelmingly positive. by which it achieves these effects in vivo, and CHEMOPROTECTIVE AGENTS its pharmacokinetic properties. A more precise OBJECTIVES In rodent models, UTL-5g lowered elevated and detailed investigation of the substance’s levels of several substances associated with toxicity has also been carried out. With positive Short-term objective: to design and identify increased toxicity following cisplatin treatment; results, measures to develop the formulation and a promising radio/chemoprotective agent blood urea nitrogen, creatinine, blood aspartate upscale production of the active pharmacological that is significantly better than what is transaminase and alanine transaminase levels, ingredients are also planned. Based on the currently available. elevated by cisplatin, all fell significantly success of this work, 21st Century Therapeutics, Long-term objective: to develop a novel drug following UTL-5g treatment, constituting a Inc. has been able to form a number of productive for chemo/radioprotection to reduce the chemoprotective effect. What is more, the partnerships in the intervening years, and has suffering of patients and increase the chemo/ agent achieved the same extent of protection secured various grants to develop UTL-5g in new radiotherapy outcome. as amifostine at a greatly reduced dosage; 60 directions in addition to pursuing its continuing mg/kg of UTL-5g was equivalent to 200 mg/kg preclinical development. KEY COLLABORATORS of amifostine. It not only avoided the apparent Dr Frederick Valeriote, researcher in cancer tumour-protective effect, but actually added Currently, Shaw and his collaborators are and radiotherapy, Henry Ford Health System, positive effects: Shaw’s researchers observed an examining the possibility of using UTL-5g Detroit, Michigan, USA increased platelet count, and a dose-dependent as a radioprotective agent.