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News Oncology


Cancer drug boost


Emma Dorey


Although chemotherapy can be effective at first, tumours can subsequently become resistant. Such is the case with Vinblastine, a drug used since the 1960s to treat lymphomas and other cancers, such as those of the bladder, ovary and lung. But now, researchers at The Scripps Research Institute (TSRI) in the US have found a way to


improve the


drug’s potency against both new and treatment-resistant tumours. The researchers made a series of analogues of Vinblastine by


could not be accomplished without the chemistry we developed,’ explains one of the researchers, Dale L. Boger, chair of the chemistry department at TSRI. The researchers discovered three analogues of Vinblastine that are 10-200-fold more potent at inhibiting cell growth across a panel of 15 human tumour cell lines. Moreover, the analogues also showed 100- 200 fold greater activity than Vinblastine against resistant tumour cells (ACS Medicinal Chemistry Letters, doi: 10.1021/ml400281w). ‘These new compounds should improve on what are already superb anticancer drugs,’ said Boger. ‘This research was carried out on cells in the lab so it’s too early to


modifying a single site (C20’) of the drug, replacing the alcohol (-OH) at C20’ with a urea (-NHCONR2


). ‘This is a site and modification that


tell if these findings could lead to better treatments for cancer patients,’ cautions Laura McCallum, science information manager at Cancer Research UK. Nevertheless, she says that altering the chemical structure of existing drugs to help make them more effective is an exciting approach that can sometimes reap rewards. ‘We look forward to the results of future research into these re-designed molecules to see if they can improve on what is already an effective chemotherapy drug,’ she says. The TSRI researchers expect that similar modifications will also boost the effectiveness of Vincristine, a closely related drug that is commonly used against childhood leukaemias and non-Hodgkin lymphomas. ‘The overall approach and the unique chemistry could be extended to other drugs as well,’ says Boger. The researchers intend to investigate the series further, to continue their preclinical development, and explore licensing opportunities for their development. Boger says the next step is to ensure they are efficacious in relevant in vivo tumour models, continue to define the structure-activity relationships in the series, and examine the functional and cellular effects of the new derivatives. Vinblastine and Vincristine, both natural products of the Madagascar periwinkle, selectively kill cancer cells by binding tubulin, the main protein constituent of microtubules. According to the researchers, before the TSRI efforts, they were viewed as too complex to be prepare by laboratory organic chemistry techniques. In 2012, Boger and his colleagues described a broad new method for modifying organic compounds like Vinblastine (Organic Letters, doi: 10.1021/ol300173v).


A growing risk Ernie Salas


ACE Westchester R


ecent pollution liability settlements have ranged from tens of millions of dollars to more than $1bn, requiring mid-sized chemical manufacturers to carefully consider their pollution exposures and reconsider their liability protections. Even multinational companies with state-of-the- art-quality controls face risks, as unintentional failures or errors affecting purity, safety and customer specifications can be financially ruinous. This is especially true for companies where inherent pollution risks cannot be separated from the product itself. As companies expand internationally, their environmental exposures continue to grow. Extra costs are sometimes incurred to replace, repair or repurchase products that companies must withdraw from the marketplace as a result of unintentional failures or damages. However, manufacturers can improve their risk protections through a series of steps, most importantly by enhancing their combined general and pollution liability protections. Many chemical manufacturers, for example, fail to recognise the need for specific environmental liability coverage, believing that this coverage is always included in standard general liability policies. An even greater number of manufacturers do not fully understand their environmental exposures. But chemical manufacturing processes, including the release of emissions and possible pollutants, represent environmental exposures to even the most responsible and compliant organisations. Within the marketplace, companies traditionally pursue individual, standalone policies to


cover these risks, including separate fixed facility and/or premises-based pollution liability policies. These coverages are often purchased in addition to their general liability coverage, but can result in coverage gaps within the primary casualty programme. Chemical manufacturers can eliminate these coverage gaps by combining their primary general liability and pollution liability coverages into one flexible insurance policy that protects against exposures related to products pollution, premises pollution and disposal pollution. Geography represents another


challenge for multinational manufacturers. Coordinating local policies across great distances and different time zones can sometimes seem to be an insurmountable obstacle.


When issuing local policies for international coverage, organisations are working with insurers, underwriters and risk managers in many different time zones and localities, each with different regulations. This underscores the importance of coordinating locally admitted liability policies across a single, global network, allowing the programme to offer expanded coverage beyond the standard US territory.


Many chemical manufacturers


have environmental exposures not covered by standard general liability policies and these environmental risks are often exposed through their products, processes or their operations. Chemical manufacturers should partner with a specialised insurance provider that understands the complex operational risks, financial risks and the evolving regulatory environment facing the global chemical industry.


Chemistry&Industry • November 2013 13


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