BioWorld International Correspondent

LONDON - A new method of improving the efficiency of treating cancer cells with targeted drugs has given such encouraging results in laboratory tests that researchers are planning a trial of the treatment in cancer patients.

The method, called gene-directed enzyme prodrug therapy, or GDEPT, involves targeting cancer cells with an enzyme, before giving a non-toxic prodrug. The enzyme reacts with the prodrug, turning it into an anticancer agent.

Researchers hope the targeted nature of GDEPT will mean fewer unpleasant side effects for patients being treated for cancer. Conventional chemotherapy can cause side effects such as nausea and hair loss.

Caroline Springer, professor of chemical biology at the Institute of Cancer Research in Sutton, UK, told BioWorld International: "We think these drugs are a very promising way forward for cancer treatment. They allow you to deliver a drug at a high concentration, which you wouldn't normally be able to do, as it is too toxic for the rest of the body."

She said that her group had been working on developing the enzyme used, and on novel prodrugs, for some time. "This latest finding shows how we can alter the chemical nature of the prodrug to make it easier for the prodrug to enter cells," she said.

Laboratory tests using a human xenograft model of breast cancer showed that one of the new treatment combinations could cure cancer, while two others could slow tumor growth.

The institute aims to start a clinical trial in cancer patients by 2006.

The work, which was funded by Cancer Research UK, is reported in the Aug. 11, 2005, issue of Journal of Medicinal Chemistry in a paper titled "Novel Fluorinated Prodrugs for Activation by Carboxypeptidase G2 Showing Good in Vivo Antitumor Activity in Gene-Directed Enzyme Prodrug Therapy."

Researchers hope that GDEPT will be more effective than antibody-directed enzyme prodrug therapy (ADEPT). Instead of targeting the tumor cells with an antibody linked to an enzyme, researchers aim to deliver the gene encoding the enzyme to the tumor using either a viral vector or liposomes. After some time has elapsed, allowing the enzyme to be expressed by the tumor cells, the prodrug is given. In cells expressing the enzyme, the prodrug will convert to its toxic form and kill the cells.

Springer and her group have worked for many years on trying to find better enzymes and prodrugs to make that concept a reality. Their earlier work included making improvements to the enzyme used for the system - a bacterial enzyme called carboxypeptidase G2 (CPG2). CPG2 cleaves a chemical bond with an activity that is unknown in mammalian enzymes.

The institute group also developed new generations of prodrugs, modifying the compounds chemically to improve their ability to enter cells. The compounds used are derived from benzoic acid; when converted by CPG2, they are converted into cytotoxic alkylating agents.

The work reported in the Journal of Medicinal Chemistry describes how the team modified the benzoic acid derivatives by adding fluorine atoms into the benzene ring. Springer said: "We found that adding two or three fluorine atoms made the prodrug variants more lipophilic and therefore better able to pass through the cell membrane."

In therapy experiments, the researchers modified breast cancer cells using a vector containing the gene for CPG2, before adding the new prodrugs. Out of eight modified prodrugs, which were tested on three variants of human breast cancer, six were effective in entering the cells, with subsequent conversion by CPG2.

Those six compounds then were evaluated in an animal model of breast cancer; again the cancer cells had been modified with the CPG2 gene. Two of those compounds brought about a substantial delay to tumor development, and another one cured two models of their tumors.

Commenting on the study, John Toy, medical director at Cancer Research UK, said: "This type of therapy should theoretically work and is showing promise. Identifying further drugs as targets for GDEPT is an important step if this treatment is to become a viable reality for patients in the future. The real test will come when the prodrugs go to clinical trials and we are able to analyze closely how well the treatment works in patients."

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