Key discoveries in natural products research and successful synthesis revolutionize the fight against cancer
In the mid-1960s, the fight against cancer was vastly different from what we know today. Scientists had yet to hamper the growth of cancer cells, clinical investigation of combination therapies for cancer had just begun, and clinical studies of anticancer vaccines had not yet started. By the late ‘70s, cancer was the leading cause of death for adults 25 to 44 years of age.
Scientists had yet to discover a way to stop cancer from growing. Neither the stabilization of microtubule assembly nor the inhibition of topoisomerase I were known to be effective ways to circumvent the uncontrolled growth of cancer cells.
Early Discovery of Potent Cytotoxic Compounds
Led by Monroe Wall, PhD, and Mansukh Wani, PhD, a team of pioneering RTI scientists reported the discovery of a compound they termed camptothecin from the Chinese tree Camptotheca acuminata. The unique mode of action for this potent cytotoxic compound was found to be the inhibition of an enzyme known as DNA topoisomerase I. Camptothecin traps this enzyme, inhibiting DNA replication and killing cancer cells.
A few years later, our team reported the structure of Taxol found in the Pacific yew tree, Taxus brevifolia. The unique mode of action for this compound was found to be the stabilization of microtubule assembly, an important step in cell division. Thus, Taxol terminates cancer cell growth.
Both compounds were discovered using the principles of bioactivity-directed fractionation, especially in vitro cytotoxicity as a predictor of in vivo efficacy. As a result, simple bioassays can be used to predict whether plant extracts or natural product compounds will have activity in human beings, helping to focus and accelerate research toward new treatments.
Revolutionizing the Battle against Cancer Cell Growth and Enabling the Pursuit of Other Bioactive Compounds
Presently, first-generation analogs of camptothecin, such as Hycamtin (topotecan) and Camptosar (irinotecan or CPT-11), marketed by GlaxoSmithKline and Pfizer, respectively, are used for the treatment of ovarian and colon cancer.
In 1992, Bristol-Myers Squibb received approval to market Taxol for the treatment of refractory ovarian cancer, and subsequently it was approved for the treatment of metastatic breast and lung cancers and Kaposi's sarcoma.
Taxol and compounds derived from camptothecin have been responsible for saving the lives of hundreds of thousands of people afflicted with cancer. In the ovarian cancer therapeutic area alone, the survival rate has more than doubled since the inclusion of Taxol in the treatment regimen.
By isolating and identifying the structure of these novel, bioactive natural products, our scientists have dramatically improved, and in some cases, lengthened or saved, the lives of cancer patients.
Our team has also used this knowledge to unearth new mechanisms of action for inhibiting cancer cell growth and to establish new principles for discovering other bioactive compounds from natural sources. These techniques are now routinely used in natural product laboratories around the world, to discover bioactive compounds from plant, marine, and fungal origins.
Taxol (a word coined by RTI's Monroe E. Wall) is a trademark of Bristol-Myers Squibb Co. Camptothecin is a trademark of RTI International.