Carlo M. Croce, MD of Jefferson Cancer Center
Some of the drugs we use to treat cancers can cause so much damage to normal cells that secondary cancers can result later in life. We are gaining insights into which drugs are the “bad actors” and protocols are being developed to attempt to reduce the use of these agents. However, the problem is not this simple. Why does the problem only occur in some patients; who is at risk and why? What type of damage do the drugs do to cells and how does this lead to the development of new cancers? Are there options to reduce the problem and if so can they be introduced rapidly into the clinic?
One of the most distressing and frequent long-term complications of cancer treatment in children and adults, is the occurrence of acute leukemia caused by the drugs and irradiation used in treating the primary tumor. Alkylating agents such as cytoxan and melphalan have long been known to cause leukemia, presumably by damaging the DNA of normal hematopoietic precursor cells in the bone marrow. A second class of drugs, those that bind to topoisomerase II, including doxorubicin and etoposide, have been associated with increasing numbers of cases of acute leukemia. The leukemia has unusual and distinctive clinical and genetic features, and is associated with a break in chromosome 11 at a gene called the mixed lineage leukemia gene (MLL). The function of that gene, the reasons for its susceptibility to damage by these particular drugs, and measures that could be taken to identify patients at high risk of leukemia and to prevent its occurrence, is the subject of this conference.
The 13th Forbeck Research Foundation Forum focused on the observation that secondary cancers can occur in patients, after they have been treated for their original malignancy. This effect is particularly marked following the administration of particular combinations of cytotoxic drugs. Most second malignancies are leukemias, and one of the groups of drugs known to cause these cancers is called ‘topoisomerase II inhibitors’. While the toxicity of these drugs is well recognized, they often form essential components of drug regimens used for the successful treatment of cancer.
The first part of the conference concentrated on how the topoisomerase II inhibitors function to prevent both cancer cells and others from functioning. It is known that these drugs and another group called topoisomerase I inhibitors act by blocking the action of particular proteins in the cells which are involved in the process of the division of DNA which occurs when cells divide. Part of the discussions revolved around the mechanisms by which cells die as a consequence of being exposed to these groups of cytotoxic drugs. More pertinent to the problem of second malignancies is what happens to cells which are damaged by the drugs but survive and ultimately become cancerous.
As indicated above, many of the secondary cancers that arise as a result of drug treatment are leukemias. The mechanism by which these occur is not clear. We can identify the cytotoxic drugs which are known to be causative agents in the development of secondary malignancies, and we know that these are capable of inducing breaks in DNA, but how this translates into cells becoming cancerous is not understood. What is clear is that large pieces of DNA can move from one chromosome to another (a process called translocation) and this occurs in a non-random fashion. The phenomenon of specific chromosomal translocations occurring in selected leukemias was discussed in detail. It is clear that the translocations observed in primary leukemias are also those which are observed in cancers arising as a result of drug treatment. One translocation which is particularly prevalent in drug induced leukemias involves chromosome 11 at position q23. A gene (a DNA sequence coding for a particular protein in the cell) intimately involved in this translocation had been identified and given the name MLL (ALL1, Htrx, or HRX). The function of this gene is not well understood but it codes for a very large protein which may interact with DNA. Studies are underway to attempt to define further the function of the gene. Unfortunately, no further insights are forthcoming as to how the action of drugs causing DNA strand breaks translates into specific translocations in leukemic cells.
Studies were also presented on the epidemiology of secondary malignancies. This means the study of populations of patients receiving chemotherapy to attempt to define those at particular risk of contracting a secondary cancer. The complexity of the problem was outlined and interesting data reviewed to try to address the problem.
The Forum resulted in an extremely lively interchange between the participants. The attendees welcomed the opportunity to discuss all aspects of studies into secondary malignancies (leukemias), the topics ranging from molecular pharmacology, genetics, protein chemistry, hematology and oncology. A consensus was agreed that where feasible, the use of high concentrations of topoisomerase II inhibitors should be avoided in cancer therapy. However, from a clinical viewpoint this is not necessarily an option until better combinations of drugs can be identified for the treatment of many different cancer types.
Quotes from Participants
“I was most impressed with the unique format of the Forum. I have never before been to a meeting that inspired (and demanded) such a vigorous and stimulating interchange between participants. I liked the format so much that I plan to institute a similar format at an MIH-sponsored meeting on the chemistry of anti-cancer drugs that I am helping to organize for next spring.” -- Neil Osheroff, Ph.D., Vanderbilt University Medical Center, Nashville, TN
"It has been a remarkable privilege and pleasure to have been part of the William Guy Forbeck Research Foundation since its inception. I have learned a tremendous amount from attending the Forums and by interacting with so many wonderful people … all of whom have made remarkable contributions to children and to improving knowledge to help our future generations.” -- Philip A. Pizzo, MD, Children’s Hospital, Boston, MA
Peter Aplan, MD
Jefferson Cancer Center
University of Wisconsin
Mary Ann Bjornisti, PhD
Thomas Jefferson University
David Crawford, MD, PhD
Carlo M. Croce, MD
Jefferson Cancer Center
Richard Fishel, PhD
Kimmel Cancer Center
John H. Kersey, MD
University of Minnesota Cancer Center
Leroy Liu, PhD
RW Johnson Medical School
Neil Osheroff, PhD
Vanderbilt University Medical Center
Yves Pommier, MD, PhD
National Cancer Institute
Les Robison, PhD
University of Minnesota
Janet Rowley, MD
University of Chicago