NEW YORK--Three types of genetic modification--chemosensitization of
cancer cells, suppression of oncogene function, and chemoprotection of
hematopoietic cells--are under study as a means of improving cancer treatment,
Albert Deisseroth, MD, PhD, said at the 15th International Bayer Pharma
Dr. Deisseroth, professor of medicine, Yale University School of Medicine,
said that adenoviral vectors that specifically infect the target breast
cancer cells have been used in preclinical studies to introduce the cytosine
deaminase gene into breast cancer cells.
The adenovirus only enters breast cancer cells that have surface proteins
necessary for the virus to enter the cell. Once inside the cell, the virus
produces proteins (cytosine deaminase) to convert the prodrug 5-fluorocytosine
(5-FC) to the toxic drug 5-fluorouracil (5-FU). When a breast cancer cell
is exposed to this virus, 70% of the prodrug is converted to 5-FU.
When hematopoietic cells containing MCS7 breast cancer cells were mixed
with the virus, 100% of breast cancer cells were killed at concentrations
of the prodrug that were not toxic to hematopoietic cells, he said.
Slowing Cancer Cell Growth
Other research is aimed at designing genetic modification procedures
that can reprogram cancer cells into less aggressive phenotypes. "Oncogenes
transmit their signals within the cell through contact with other proteins,"
Dr. Deisseroth said. "We identified two small peptides that, when
overexpressed in chronic myelogenous leukemia cells, suppress growth factor."
The researchers introduced such inhibitory molecules of the transforming
protein into leukemia cells to test if their presence would reduce growth
in cultures. Growth decreased as the ratio of inhibitory molecule was increased,
he said. The next step is to see if virus vectors can deliver these inhibitory
peptides to leukemia cells in a mouse model, he said.
Chemoprotection via MDR Genes
Dr. Deisseroth also reported studies of genetic modification designed
to reduce the myelotoxicity of chemotherapy. For example, in animal studies,
the administration of paclitaxel (Taxol) caused the white cell count to
drop to zero in control mice.
In mice in which the hematopoietic cells had been exposed to retroviral
vectors containing the multidrug-resistance (MDR-1) gene and returned to
the mice, the first exposure to chemotherapy produced a dramatic reduction
in the sensitivity of the hematopoietic cells to chemotherapy. After subsequent
exposures, there was total resistance to the chemotherapy.
The technique is now being studied in humans. In one trial, the MDR-1
gene was introduced into the normal hematopoietic cells of patients with
advanced breast and ovarian cancer. The trial demonstrated that retroviral
vectors can be used for this purpose and that it is possible to engraft
such cells into patients after intensive systemic therapy.
"We also found that genetic modification did not damage the ability
of the hematopoietic cells to repopulate, indicating no damage to normal
cells. Furthermore, evidence of the genetically modified cells were found
after transplant," he said.
In a future trial, the researchers will study patients with breast cancer
whose clinical features predict that they will relapse after surgical resection
and that the relapsed cells will be resistant to conventional-dose therapy.
Before intensive chemotherapy, bone marrow cells will be collected,
modified genetically to confer resistance to chemotherapy, and returned
to the patients, who will then receive rapidly escalating doses of paclitaxel.
"This technique will allow us to avoid the risk and toxicity generated
by intensive chemotherapy," he said.