NEW YORK (Reuters Health) - A new study in dogs shows administering hematopoietic cells modified with a drug-resistance gene prevents the myelosuppression normally seen with a temozolomide-based chemotherapy combination.
Based on the findings, researchers at the Fred Hutchinson Cancer Research Center in Seattle have begun a clinical trial of drug resistance gene therapy in patients with glioblastoma, Dr. Hans-Peter Kiem, the study's lead author, told Reuters Health.
Autologous stem cell transplants have been used to avoid the myelosuppression that occurs with high-dose chemotherapy, Dr. Kiem and colleagues note in the February 1st issue of Blood. But the number of high-dose chemotherapy cycles that can be given with this approach is limited, and myelosuppression does occur for short periods.
"In contrast, a genetically protected bone marrow could make possible tightly spaced dose-intense chemotherapy regimens over extended time periods in the complete absence of any myelosuppression," Dr. Kiem and his team write.
"For these alkylating agents, we think now the more we can give the better," Dr. Kiem told Reuters Health.
The researchers transduced stem cells with a mutation of the methylguanine methyltransferase (MGMT) gene, P140K, and then administered CD34+-selected cells to two dogs. MGMT is a DNA-repair enzyme that confers resistance to nitrosoureas and methylating agents. The P140K mutation promotes resistance to a combination of these chemotherapy drugs with the MGMT inhibitor O6-benzylguanine (O6BG).
"In both animals, gene marking increased after repeated doses of O6BG and temozolomide from a moderate baseline to levels greater than 98% in granulocytes," Dr. Kiem and colleagues write. "Durable increases in marking were also observed in lymphocytes, red blood cells, platelets, and BM CD34+ cells."
While clinical trials have shown the maximum tolerated dose of the temozolomide to be 472 mg/m2, and myelosuppression resulted in dogs given doses of 500 mg/m2 and 600 mg/m2, animals given the gene-modified stem cells tolerated doses up to 800 mg/m2 with only mild or no thrombocytopenia.
"There's no evidence that there is any malignancy or leukemia," Dr. Kiem said. The findings are particularly exciting, he noted, because temozolomide is used in a number of different malignancies, including glioblastoma and melanoma.
In the clinical trial now underway, Dr. Kiem and his colleagues are giving patients a single dose of chemotherapy before infusing them with the modified stem cells, with a second dose 4 to 6 weeks later. They are beginning with the maximum tolerated dose of 472 mg/m2 and will increase until any dose-limiting toxicities are seen.
In an accompanying editorial, Dr. Stanton L. Gerson of Case Western Reserve University calls the findings "an important advance in the field of hematopoietic stem cell therapy." While researchers have done similar studies in mice, he points out, Dr. Kiem and colleagues are the first to show the approach can work in a large animal.
"These data support ongoing efforts to begin human clinical trials transducing stem cells with the MGMT (P140K) drug selection gene by retroviral and, eventually, lentiviral gene transfer for cancer and perhaps nonmalignant conditions," Dr. Gerson concludes.
Source: Blood 2005;105:914,997-1002. [ Google search on this article ]
MeSH Headings: Animal Diseases : Antineoplastic Agents, Combined : Biological Therapy : Bone Marrow Cells : Disease Models, Animal : Genetic Engineering : Genetic Techniques : Investigative Techniques : Pancytopenia : Therapeutics : Gene Therapy : Analytical, Diagnostic and Therapeutic Techniques and Equipment : Diseases