In the Feb. 15 issue of Cancer Research, NCI researchers Dr. Masanori Onda, Dr. Ira Pastan, and colleagues report the anticancer activity of their recombinant immunotoxin (RIT) against human breast cancer, osteosarcoma, and neuroblastoma cell lines. This work was done in collaboration with Dr. Nai-Kong Cheung at Memorial Sloan-Kettering Cancer Center who isolated the original antibody. A RIT is a fragment of a genetically altered monoclonal antibody that is fused to a toxin. These compounds hold potential as anticancer therapeutics because they combine the specific targeting of an antibody with the cytotoxic effects of a plant or bacterial toxin. Dr. Pastan's group has previously completed phase I clinical trials for two other RITs in patients with leukemia, Hodgkin's disease, and lymphoma. Very high complete response rates were observed in drug resistant hairy cell leukemia with RIT BL22. The new RIT, called 8H9(Fv)-PE38, uses the same toxin as these two previous molecules in conjunction with a different specific antibody. Not only did this RIT show anticancer activity in cell lines, but it also demonstrated specific antitumor activity in mouse xenograft models for human breast cancer and osteosarcoma.
The researchers slightly modified 8H9(Fv)-PE38 in order to increase its stability and yield as well as to make it a better drug candidate. This new RIT was tested for toxicity in monkeys, since mouse studies have not always been useful in predicting human toxicities. Based on these experiments, Dr. Onda indicated that the RIT "has low toxicity for liver and is worthy of further clinical development."
A gene that is known to promote cancer appears to play a very important role in the development of multiple myelomas and may prove to be a fruitful target for therapies aimed at treating these blood cancers, according to a study published in the February 2004 Cancer Cell. Multiple myeloma is the second most prevalent blood cancer after non-Hodgkin's lymphoma, representing approximately 1 percent of all cancers and 2 percent of all cancer deaths.
Studies have established that abnormal forms of the gene implicated in the study, c-maf, are present in approximately 5-10 percent of patients with multiple myeloma. However, in the Cancer Cell study, led by Dr. Louis M. Staudt of the Metabolism Branch in the NCI Center for Cancer Research, researchers were surprised to find that the normal form of c-maf was present in more than 50 percent of the multiple myeloma cell lines and in exactly 50 percent of the bone marrow samples they analyzed.
Based on these findings, the research team attempted to delineate what role c-maf may play in myeloma progression, including tumor growth. In both laboratory tests and mice, c-maf was vital to myeloma cell proliferation. In addition, c-maf increased the production of an adhesion protein that helps myeloma cells interact with normal cells in the bone marrow, known as stromal cells. Myeloma cells rely heavily on signals from stromal cells to proliferate and survive. Perhaps most important was the finding that in immunodeficient mice, inhibiting c-maf actually prevented myeloma cell progression and tumor development.
"Our results indicate that overproduction of c-maf is one of the most common abnormal events associated with myeloma," said Dr. Staudt. "Further, our finding that inhibition of c-maf blocks myeloma proliferation and tumor formation makes c-maf an intriguing and exciting novel target for future therapies."
Researchers at the Harvard School of Public Health, Yale University School of Medicine, and the Johns Hopkins Medical Institutions have found indications that regular aspirin use may protect against Hodgkin's lymphoma by inhibiting a transcription factor that is necessary for immune function and the survival of Hodgkin's lymphoma cells.
In the population-based, case-control study - published in the Feb. 18 issue of the Journal of the National Cancer Institute - regular aspirin use was associated with a 40 percent reduced risk of Hodgkin's lymphoma, as compared with nonregular aspirin use. The association was consistent across subgroups of age, sex, race, religion, smoking history, and analgesic use. Unlike aspirin, the use of other nonsteroidal anti-inflammatory drugs (NSAIDS), such as ibuprofen, was not statistically significantly associated with Hodgkin's lymphoma risk. However, regular acetaminophen use, compared with nonregular use, was associated with a consistently higher risk of Hodgkin's lymphoma.
The research team, led by Dr. Ellen Chang at the Harvard School of Public Health (now with the Karolinska Institute in Sweden), concluded that the findings "may indicate that properties exclusive to aspirin are responsible for its relationship with Hodgkin's lymphoma," particularly aspirin's ability to inhibit the transcription factor NF-κB. The study should be interpreted with caution, the researchers noted, because of limitations such as the fact that patients were only questioned about the last five years of medication use and an "insufficient power for detailed dose-response analyses."