Author | Eric K. Rowinsky, MD


Commentary (Patnaik/Rowinsky)-Epidermal Growth Factor Receptor Inhibitors for the Treatment of Colorectal Cancer: A Promise Fulfilled?

April 01, 2004

The past decade has given rise toan explosion of rationally designed,molecularly targetedtherapeutic agents. The epidermalgrowth factor receptor (EGFR) hasserved as the principal platform forthe development of such novel targetedtherapies, resulting in a paradigmshift in the treatment of a vast array ofsolid malignancies. Damjanov andMeropol have provided a comprehensiveand insightful overview of the roleof EGFR-directed therapeutics in colorectalcancer. They have chosen tofocus their discussion on the compoundsthat are furthest along in clinicaldevelopment and, hence, havereviewed the monoclonal antibodiescetuximab (Erbitux), ABX-EGF, andEMD 72000, as well as the small-moleculetyrosine kinase inhibitors gefitinib(Iressa) and erlotinib (Tarceva).

Novel Radiation Sensitizers Targeting Tissue Hypoxia

October 01, 1999

That hypoxic tissues are more resistant to the effects of radiation than well-oxygenated tissues has been known for many decades, and repeated in vitro demonstrations have confirmed that to achieve the same degree of cytotoxicity, hypoxic cells require about three times the radiation dose that well-oxygenated cells need. Hypoxic cell sensitizers enhance the tissue response to standard radiation, generally by mimicking the effects of oxygen, which induces the formation and stabilization of toxic DNA radicals. Although many hypoxic cell sensitizers like the nitroimidazoles have been evaluated in combination with radiation, these agents have had no or only minimal therapeutic impact due to either their limited potency or their toxicity at biologically relevant concentrations. This article reviews several new modalities that either increase oxygen delivery or sensitize hypoxic tissues. These modalities, all currently in early clinical evaluations, include: (1) tirapazamine, a bioreductive agent; (2) gadolinium texaphyrin, a hypoxic cell sensitizer with biolocalization properties using magnetic resonance imaging; (3) RSR13, an allosteric modifier of hemoglobin; and (4) bovine hemoglobin modified by the attachment of polyethylene glycol polymers.[ONCOLOGY 13(Suppl 5):61-70,1999]

Alternative Dosing Schedules for Irinotecan

August 01, 1998

Most of the clinical experience with irinotecan (CPT-11 [Camptosar]) has been with either a weekly or an every-3-week schedule. Recent phase I trials have explored new routes and schedules of administration. One approach

Clinical Status and Optimal Use of Topotecan

November 01, 1997

The development of topotecan (Hycamtin) and the encouraging preliminary results of its use in clinical trials are comprehensively reviewed by Takimoto and Arbuck. The successful development of topotecan demonstrates that focused research and developmental efforts by the pharmaceutical industry in anticancer therapeutics can actually “pay off.” Approximately 15 years ago, the prototypic topoisomerase I inhibitor camptothecin was “placed back on the shelf” because it induced severe, unpredictable toxicity when administered as a sodium salt (sodium camptothecin). After recognition that camptothecin was active by virtue of a novel mechanism of action (topoisomerase I inhibition), developmental research efforts at SmithKline Beecham led to the synthesis of a myriad of camptothecin analogs, significant structure-function information, and the ultimate selection of topotecan as a lead camptothecin analog for clinical development.[1-3]