Annual Forum 1987 – Reasons for Drug Failure

Bruce Chabner, MD, National Cancer Institute, Bethesda, MD

Giovanna Ferro-Luzzi Ames, Ph.D., University of California, Berkeley, CA
Bruce Ames, Ph.D., University of California, Berkeley, CA
Bruce A. Chabner, MD, National Cancer Institute – Div. of Cancer Treatment, Bethesda, MD
Tito Fojo, MD, National Cancer Institute – Div. of Cancer Treatment, Bethesda, MD
Michael Gottesman, MD, National Cancer Institute – Div. of Cancer Biology and Diagnosis, Bethesda, MD
John S. Holcenberg, MD, Children’s Hospital of Los Angeles, Los Angeles, CA
Susan B. Horwitz, Ph.D., Albert Einstein College of Medicine, Bronx, NY
Victor Ling, MD, The Ontario Cancer Institute, Toronto, Canada
Charles Myers, MD, National Cancer Institute – Div. of Cancer Treatment, Bethesda, MD
Ira Pastan, MD, National Cancer Institute – Div. of Cancer Biology and Diagnosis, Bethesda, MD
Barry Rosen, Ph.D., Wayne State University School of Medicine, Detroit, MI
Howard Shuman, Ph.D., Columbia University, New York, NY
Takashi Tsuruo, MD, Japanese Foundation for Cancer Research, Tokyo, Japan

Layout and Goals

  1. Introduction
  2. Transport Genes an Drug Resistance
  3. Multidrug Resistance and Carcinogenesis
  4. Clinical Studies of MDR
  5. Discussion of Approaches to Clinical Trials

In November, 1987, the third annual Forum will deal with reasons for chemotherapy failure, a very important matter in attempts to improve the treatment for patients with cancer. Why do drugs work in one patient and not in another? Why in one patient will the tumor initially respond, and virtually disappear, and then recur in a matter of months or years with cancer cells that are resistant to those very same drugs? Are there ways to avoid drug resistance? When drug resistance occurs, are there maneuvers to overcome this resistance?

We know there are certain areas of the body, such as the brain, that are chemotherapy sanctuaries. This means that the drugs do not penetrate into these areas. Does this also play a role in drug failure? If inroads can be made in answering these questions, then chemotherapy treatment of patients with cancer will improve and the overall cure rate will also improve. The Forum on Reasons for Drug Failure will be chaired by Dr. Bruce Chabner, Director of the Division of Cancer Treatment at the National Cancer Institute, and one of the outstanding cancer pharmacologists in the world.

Outcome Report
Scientists from the United States, Canada and Japan met in November 1987 at Moss Creek Plantation in Hilton Head, South Carolina, to discuss multidrug resistance in cancer chemotherapy in the third Annual Think Tank of the William Guy Forbeck Foundation. The participants discussed the biochemistry and genetics of a special form of resistance to cancer chemotherapeutic drugs now known as multidrug resistance (MDR). MDR was first discovered by Dr. Victor Ling at the University of Toronto, who was the first to appreciate that cancer cells could become resistant to traditional chemotherapeutic drugs by developing a unique protein on the cell membrane. This protein functions to rid the cell of potentially toxic or dangerous compounds, and extrudes cancer drugs, among other compounds. Since Ling’s discovery, approximately 10 years ago, evidence has accumulated implicating this protein, P170, is resistant to a variety of cancer drugs, including some of the most effective agents for treating leukemia, lymphoma and childhood tumors.

The meeting was as called to bring together prominent researchers in this field to consider ways in which these results might be applied to improving cancer treatment in patients. The initial sessions of the meeting discussed the P170 glycoprotein and the genetic factors that control its expression in tumor cells. Investigators from Toronto, the National Cancer Institute in Bethesda, Maryland, and Cancer Chemotherapy Center in Tokyo presented their latest studies describing the gene that codes for this protein and initial work on its presence in a variety of human tumors. The protein is found in leukemia cells after treatment, in lymphomas after treatment, and in certain solid tumors, such as colon cancer, kidney tumors and adrenal gland tumors, both before and after treatment. More recent work subsequent to this meeting has now defined an important role for the MDR protein in additional diseases, including multiple myeloma. As a result of the meeting, clinical studies of P170 expression were initiated in the Pediatric Cooperative Groups and in Acute Leukemia Treatment groups.

The meeting considered analogous transport proteins in lower organisms, including a series of bacterial membrane-associated transporters. Dr. Giovanna Ames from the University of California presented evidence that P170 protein has homology in its ATP binding regions with histidine and multose permease systems in bacteria, and proposed that it might represent a fusion of two transmembrane subunits of the bacterials permeases; possibly the bacterial protein has since been adapted for other functions in mammalian cells.

Work by Susan Horwitz at Albert Einstein College of Medicine evoked considerable interest. She showed that a radioactive calcium channel-blocking compound, azidopine, could be used to label the protein at the drug surface. This test is now widely used in studies of drug binding to P170 and, indeed, to identify the presence of the protein in tissues.

Alternatives to P170 as the use for multidrug resistance were then discussed by investigators from the National Cancer Institute. Charles Myers, Chief of the laboratory of Clinical Pharmacology, provided evidence that of other proteins, including glutathione – S- transferase, are altered in drug-resistant cells, and raised the possibility that these enzymes could contribute to multidrug resistance. Subsequent work has clearly shown that this is the case and has implicated a set of DNA-cleaving proteins, called topoisomerases, as alternative causes of multidrug resistance.

In summary, the conference provided a special opportunity to consider developments in this rapidly evolving field. Collaborations between various investigators were established, particularly with respect to sharing reagents such as DNA probes and antibodies, and collaborative experiments were begun in the area of genetics and clinical laboratory collaborations.

The fruits of this meeting were much in evidence at a recent conference on the subject (April 10-11, 1989, in Bethesda), where the Forbeck participants presented the results of a number of collaborative studies. Among these, the work of Ronnison from the University of Illinois, Pastan, Gottesman and Fojo from the NCI, Horwitz from Einstein, Tsuruo from Tokyo, and Ling from the University of Toronto provided further evidence for a role of the P170 protein in clinical drug resistance and the possibility of reversing drug resistance with antibodies and calcium channel-blocking drugs.