Antibody-drug conjugates: not exactly “smart bombs” for cancer
Jun22

Antibody-drug conjugates: not exactly “smart bombs” for cancer

I only have a quick post today because I really want you to spend your reading energy on a superb C&EN cover story by my colleague here, Lisa M. Jarvis. The media frenzy that normally follows the American Society of Clinical Oncology (ASCO) meeting each June focused this year on cancer cell-directed antibodies conjugated to highly-cytotoxic compounds. The most ballyhooed of these is T-DM1, the anti-HER2 trastuzumab antibody (Herceptin) covalently linked to the microtubule-inhibiting maytansine analog, DM1 (meeting abstract, Genentech press release). When the conjugate is internalized by breast cancer cells overexpressing the HER2 protein, the highly-toxic DM1 drug is released intracellularly. The study population was 991 breast cancer patients whose disease was previously treated with plain old trastuzumab and a taxane (such as paclitaxel or docetaxel). In this, the EMILIA study, patients were randomized to receive T-DM1 or a combination of capecitabine (Xeloda) and lapatinib (Tykerb). Relative to the latter group, the DM-1-treated patients had a 35 percent increase in "progression-free survival," the time from treatment to worsening of the disease or death (9.6 months vs. 6.4 months). The T-DM1-treated patients also experienced a reduction in serious adverse effects (40.8 percent vs. 57.0 percent). Large media organizations promoted this drug as a "smart bomb" or "wonder drug." The truth, as Jarvis reports, is that this promising technology is still in the experimental phase following the 2010 withdrawal of the first FDA-approved ADC, Mylotarg, due to severe liver toxicity and poor treatment response in acute myeloid leukemia (AML). Don't get me wrong. The ADC field is fascinating and full of promise. But mainstream-media editors who simplify headlines have oversold the findings, potentially misleading patients who might not read all of the study details. Moreover, the T-DM1 findings are in abstract form at this point. The comprehensive article by Lisa Jarvis details some of the technical challenges in creating ADCs but the high promise of these therapies based on the breadth of companies with ADCs currently in development. Go and read. Disclosure: The primary author of the ASCO report, Duke oncologist Dr. Kim Blackwell, is a family friend and colleague. I also had a professional interest in antibody-drug conjugates while working at RTI and was co-author on a paper with investigators from Seattle Genetics in this regard. Reference: Jarvis, Lisa M. Rethinking antibody-drug conjugates. Chemical & Engineering News 90(25): 12-18 (18 June...

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De-caffeinating pills? Say it ain’t so, Think Geek
May18

De-caffeinating pills? Say it ain’t so, Think Geek

Let me state unequivocally at the outset: I LOVE Think Geek. This purveyor of hip nerdgear - "Stuff for Smart Masses" - has saved me every Christmas, the occasional birthday, and brought me great personal pleasure with their clever offerings. But most important to me about Think Geek is that I know when giving a gift from them, I am giving someone solid science. A mini Van de Graaff generator. A USB plasma ball. And when my office visitors encounter my LED binary clock, I'm asked, "What the heck is that?" My next two purchases are likely to be the Pet's Eye View Digital Camera for the PharmBeagle and the DIY Guitar Pick Punch for me (even though you could buy 80 top-quality guitar picks for the same price). But I will not be buying Rutaesomn® Sleep Aid - De-caffeinating Chill Pills. The product is billed as being a pill that speeds metabolism of caffeine from your day-long coffee and energy drink binges. Take it 2-4 hours before you want to go to sleep, "helps get rid of caffeine in your body keeping you awake." Well, what is it exactly? Rutaesomn® is an herbal extract from Evodia rutaecarpa that is also known in Chinese traditional medicine as Wu Zhu Yu where it's used for alleged weight-loss activity. The biologically-active chemical in the herb is called rutaecarpine. So, what does this have to do with caffeine? Well, rutacarpine influences the activity of our major caffeine-metabolizing enzyme called CYP1A2. This is one of a family of over 50 such enzymes that allow us to handle drugs and chemicals we've encountered throughout our evolution, including even chemicals that haven't yet been made. These CYPs, or cytochrome P450 enzymes, could be thought of as the catalytic converters of the body. You'll find them mostly in the liver and kidney but almost every cell of your body has some small amount. Most of the time they change chemicals into their less active forms (though there are important exceptions where they make drugs more active or even carcinogenic). Usually, the CYP clips off or modifies a part of the chemical to make it more water-soluble and, therefore, more easily excreted in the urine. This is how CYP1A2 works to metabolize and inactivate the stimulant activity of caffeine. But if you do a little reading, you'll learn that rutaecarpine is an inhibitor of CYP1A2. Wait a minute. Doesn't that mean that rutaecarpine would increase the length of caffeine action in the body? Wouldn't taking rutacarpine keep you awake longer after a caffeine binge? Well, yes, if it's taken in a high enough dose. But here's what...

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How Do You Like Your Caffeine?
Mar08

How Do You Like Your Caffeine?

Inhaled or oral? Natural or synthetic? Two interesting reports came across the interwebs over the last couple of days. Earlier this week, the US Food and Drug Administration issued a warning letter (press release) to makers of Aeroshot brand of inhaled caffeine. No, it's not an asthma medicine (although oral theophylline is). It's billed as a non-caloric caffeine delivery system, 100 mg per hit. That's roughly the amount in two 12 fl oz/355 mL cans of Mountain Dew or one gulp more than a 8.4 fl oz/250 mL can of Red Bull energy drink. However, the company claims that only 15-25 mg are delivered - perhaps half the amount in a Coca-Cola. The FDA has concerns about the dual promotion of the product for swallowing and inhalation, the relative safety of inhaled caffeine, and the potential for children and adolescents to use the product in combination with alcohol. The company's FAQ specifically notes that the product is not marketed for use in children. Readers will recall that Four Loko caffeinated alcohol drinks were withdrawn from the market in late 2010 and replaced with alcohol-only versions. On another front, Analytical Chemistry published a paper by a group led by Maik Jochmann at Essen, Germany on an isotopic ratio method for determining whether caffeine in a consumer product is derived from plants or synthetically. While public demand for naturally-caffeinated products doesn't seem to be especially a big deal in the US, the FDA only requires listing of caffeine content for products with added synthetic caffeine. (Note: I only just found out this afternoon that C&EN Online had covered this paper back on February 29th. My apologies to all for not linking to it. That report is here.) The authors show here that 13C ratios can indeed be used to determine the source of caffeine. In general, 13C represents 1.11% of Earth's carbon. However, plants incorporate less 13C in making caffeine via C3 carbon fixation from atmospheric carbon dioxide. I'm still a bit unclear as to whether the method can determine the difference between naturally-occurring caffeine from products spiked with purified, plant-derived caffeine (I don't think so). In the paper, I learned something new and of relevance to the American South (where I live): the international standard for 13C/12C ratios is Vienna Pee Dee Belemnite (VPDB). In 1957, the late Scripps Institution of Oceanography geochemist Harmon Craig, defined terrestrial carbon isotope ratios from a fossilized cephalopod in the Pee Dee limestone formation of South Carolina. Although none of the original specimen remains, secondary standards are now used for calculations. To complete our history lesson, you should know that the Pee Dee River...

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Talking fungi at Skeptically Speaking
Feb05

Talking fungi at Skeptically Speaking

Well, if you're looking for something to do during Super Bowl halftime than watch Madonna, you're welcome to join me online for the wildly-successful science radio show, Skeptically Speaking. With Edmonton-based host Desiree Schell (@teh_skeptic) and her US-based producer K.O. Myers (@KO_Myers), we'll be discussing the secret lives of fungi, particularly as related to the synthesis of secondary metabolites that we use as therapeutic agents. If you're able to join us live, we'll be at this UStream.tv page at 8 pm Eastern, 6 pm Mountain. On the chat bar at the right of the page, you can follow the online discussion and submit questions of your own. I hope that you can dial us in. If not, the complete podcast will be downloadable on the evening of February...

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NCCU Dinner with Discoverers: Chemist, Dr. Mansukh Wani
Nov05

NCCU Dinner with Discoverers: Chemist, Dr. Mansukh Wani

The NCCU Eagles RISE program is a NIH/NIGMS research education program for which I serve as principal investigator at North Carolina Central University in Durham. When I moved to the Research Triangle area, I had the opportunity to work as a pharmacologist with the late Dr. Monroe Wall and Dr. Mansukh Wani, scientists who with colleagues discovered the anticancer compounds, taxol and camptothecin. I first came to know of Dr. Wani while I was a graduate student in 1987 while attending a DNA topoisomerase chemotherapy conference at NYU in Manhattan. To be honest, I was too nervous to even introduce myself to this legend of natural products chemistry. Almost 25 years later, I am now blessed to call him a family friend. One of the other joys I have is sharing the now 86-year-old Dr. Wani and his story with my students. Here's a recap of our visit with him as posted on our NCCU Eagles RISE blog:   On the evening of October 26th, we had the remarkable pleasure to have dinner with Dr. Mansukh Wani, Chemist Emeritus of RTI International (formerly Research Triangle Institute). Together with his longtime collaborator, the late Dr. Monroe Wall, Dr. Wani and colleagues isolated and determined the structures of the anticancer drugs Taxol and camptothecin. Taxol has been a mainstay in the treatment of breast and ovarian cancer while camptothecin gave rise to two, semi-synthetic FDA-approved drugs: topotecan (Hycamtin) and irinotecan (Camptosar). For these discoveries they received numerous awards culminating in the naming of the RTI Natural Products Laboratory as a National Historic Chemical Landmark of the American Chemical Society in 2003. The landmark application was led by Dr. Nick Oberlies, now in the Department of Chemistry and Biochemistry at the University of North Carolina at Greensboro; Nick and I reformulated the application and supplementary historical information into a 2004 review article in the Journal of Natural Products (DOI: 10.1021/np030498t) In this interview for an Indian publication in the Research Triangle, Dr. Wani shares what it was like to move to North Carolina in 1962. He graciously accepted our invitation to tell these and other stories to us at Sitar Indian restaurant, a Durham favorite. Rather than recap his discussion of his career, we thought it would be more valuable to share with you student insights from their evening with this remarkable, warm, and humble man. From Adama Secka, M.S. Candidate, Pharmaceutical Sciences: Wednesday, October 26th 2011 will be a day that I will always remember for the rest of my life; I met the most incredible man in our science world. He was most genuine, kind, patient, and supportive - I mean he is...

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Bryostatins: Panacea?
Oct24

Bryostatins: Panacea?

I just had the delightful pleasure of participating in the C&EN Advisory Board meeting late last week. Among the outstanding C&EN writers and editors at the DC headquarters, I got to meet several others who are stationed around the US and the world. One of these new friends based in New Jersey, Bethany Halford, has this week's C&EN cover story on the marine natural products, the bryostatins. These complex compounds were originally studied for anticancer activities but, as Bethany tells us, are now showing promise in animal models of Alzheimer's disease. And while Bethany tells us that the first bryozoan source of these compounds was collected in 1968 from Gulf Specimen Co., she resisted the urge to tell us that the company is in Panacea, Florida. (Here's a definition and etymology of panacea.) Go forth and read. References: Halford, Bethany. Chemical & Engineering News 89(43): 10-17 (24 October 2011) Cover story - The Bryostatins' Tale Profile on George (Bob) Pettit - Pioneer: Undersea Treasure Hunter Natural product drug development - Drug Development: Taking the Long...

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