Lippard Discusses Cancer Therapy at TBP Lecture
Chemistry Department Head Stephen Lippard discussed his lab’s contributions toward the fight against cancer at the inaugural annual Tau Beta Pi lecture titled “Drug Discovery -- From Serendipity to Rational Design in the Hands of Chemists.”
Lippard’s research has recently formed the basis for a Phase I clinical trial that will likely begin late this fall in conjunction with the Dana-Farber Cancer Institute. Patients will undergo a combination therapy that will include cisplatin -- a Platinum containing anti-cancer drug -- progesterone and/or estrogen. The exact details of the clinical trial have yet to be hammered out. For instance instead of cisplatin, an FDA-approved analog -- carboplatin -- may be used. Clinicians also have yet to decide whether they will use estrogen or progesterone or so combination of the two.
Cisplatin has formed part of Lippard’s research since the 1970s. “It would be a very rewarding experience if many years of fundamental research were to have a practical consequence in the treatment of some forms of cancer,” Lippard said.
A metabolite of cisplatin acts by inducing a conformational change in DNA. A working model for the mechanism of action of cisplatin postulates that the induced bend allows binding of proteins which contain the HMG (high mobility group) domain. Binding of the HMG domain protein in turn may prevent repair mechanisms within the cell that would otherwise remove cisplatin from the DNA. By limiting this process, according to the model, DNA replication and consequently cell division will not occur. Blocking of replication sets off signals within the cell that lead to programmed cell death.
“Just binding to DNA is not sufficient” due to repair mechanisms in the cell, Lippard said.
Rationale for the concomitant administration of the hormones progesterone or estrogen and cisplatin came from the idea that overexpression of HMG in cells would increase the efficacy of cisplatin in the treatment of cancer.
Unpublished work from Lippard’s laboratory confirmed a previous report in the scientific literature of increased levels of HMG1 (the first HMG domain protein ever isolated) in estrogen induced cells. HMG1 acts as a chaperone that helps form the active estrogen receptor. While not studied, a feedback mechanism could be at work in which an an increase in estrogen levels increases production of HMG1 to help in formation of active estrogen receptors.
Cisplatin was first discovered to be effective in arresting cell division -- and thereby a possible weapon in stopping the proliferation of malignant tumors -- by physicist Barnett Rosenberg of Michigan State University. Rosenberg came across a picture of dividing cells which resembled the pattern produced by iron filings in a magnetic field.
This observation led to studies of the effect on cell division in E. Coli by an electric field. In what Lippard pointed out in his talk as a striking example of serendipitous discovery, researchers found that the cells formed into long filaments. The cells grew but could not divide.
However, as Rosenberg’s group first postulated, it was not the electric field itself that caused this unusual result but chemicals formed as a result of the apparatus set-up. The researchers used platinum anodes directly applied to the cell culture media to create the electric field. Reactions between the platinum anode and this broth resulted in the formation of cisplatin.
Rosenberg isolated this cisplatin and used it to test lab mice with malignant tumors. Mice who did not receive cisplatin treatment died. tumors in mice who received cisplatin decreased in size.
Cisplatin is most commonly used in the treatment of testicular cancer. Like many anti-cancer treatments, cisplatin does not distinguish between cancerous and non-cancerous cells.
“It’s not like the lock and key mechanism of an enzyme,” said Chris Zeigler a postdoctoral associate working with Lippard. Cisplatin acts by binding adjacent guanine nucleotides (GG) in DNA. GG repeats occur often in DNA gene sequences.
The clinical studies of cisplatin hormone combination therapy have a two fold purpose: to assess the possible toxicity of combining the treatments and to assess HMG levels in patient biopsy tissue, according to Lippard. Study of the HMG levels will help to assess the validity of this particular model of cisplatin action in humans.
Phase I clinical studies in general represent the “initial introduction of an investigational new drug into humans,” according to the Food and Drug Administration. The number of subjects in Phase I clinical studies generally range from twenty to eighty.
Cisplatin analog search continues
The search for cancer treatments, however, has not ended with this Phase I trial. Lippard also discussed his lab’s efforts toward the high-throughput isolation of platinum-containing cisplatin analogs that might also be effective in cancer treatment.
In the course of this past summer, researchers in his lab have isolated about 3,600 such compounds. According to scientific literature, in cisplatin’s 30-year history, about 3,000 analogs have been isolated and characterized. Lippard described these efforts as “planned serendipity, but where serendipity is beat by numerology.”
“We can match in three months” what took place of over the course of 30 years, said Ziegler, who is in charge of synthesizing the combinatorially produced compounds and assaying for their activity.
The technique has provided the basis for a patent application, according to Zeigler. Researchers may use the production and screening process of the cisplatin analogs to start a company.