Jun 9 2005
The search for new drugs to fight cancer remains at the top of the to do list for pharmaceutical researchers. A recent variation is polymer chemotherapy agents, drugs that have been attached to a "backbone" of long chain molecules.
A British team has now gone a step further, grafting two different drugs to the same backbone. In this way, a cytotoxic agent and a hormone therapy drug have been unified into a molecular tandem team to synergistically fight against estrogen-dependent breast cancer.
The study was published online May 24, 2005 in the journal Angewandte Chemie International Edition.
The "polymeric delivery form" of chemotherapy drugs has advantages: the bulky molecules do not move from the blood into healthy tissue as easily as small molecules. The drugs still reach the tumor cells well enough because the freshly formed blood vessels in tumors are significantly more permeable than normal veins—the healthy tissue is protected. When bound to polymer chains, agents are less toxic than in their free form. In addition, they cannot be cracked as easily by the tumor cells' resistance mechanisms. The first synthetic polymer chemotherapy drug to reach the clinical testing phase was a conjugate of the well-tolerated N-(2-hydroxypropyl)methacrylamide and the proven cytotoxic Doxorubicin (Dox). In order to increase its effectiveness against breast cancer, the team headed by Ruth Duncan and María J. Vicent thought the drug should be combined with another drug, a hormone therapy agent. Most cases of breast cancer are of the hormone-dependent type; estrogen promotes the growth of the tumor. The tumor cells are not dependent on an external source of estrogen—they produce the hormone themselves. One way to stop the hormone from working is to stop its biosynthesis with an aromatase inhibitor.
The researchers thus attached the cytotoxic Dox and the aromatase inhibitor aminoglutethimide to the same polymer backbone. The short, tailor-made peptide chains that fasten the drugs to the backbone play an important role in this. While traveling through the blood vessels, they must bind the drug molecules tightly to the backbone; within the cells, they must be cut by enzymes in order to release the active molecules.
"Our polymer conjugate," says Duncan, "which is the first to combine hormone therapy and chemotherapy, proved to be significantly more cytotoxic against a line of tumor cells than a mixture of the two individual drugs in polymer form."
Article: "Polymer Therapeutics Designed for a Combination Therapy of Hormone-Dependent Cancer," Maria J. Vicent, Francesca Greco, Robert I. Nicholson, Alison Paul, Peter C. Griffiths, and Ruth Duncan, Angewandte Chemie International Edition; Published Online: May 24, 2005.