OVER THE PAST TWO decades anti-cancer drugs have become available in growing numbers. Chemotherapy is a household word and, although there are no hard statistics, officials at the National Cancer Institute estimate hundreds of thousands of Americans are receiving it.
How do such drugs evolve? How do they get to the consumer? What are the researchers really looking for?
The lowest common denominator is the quest for safe effectiveness - for powerful agents that will selectively kill the malignant cells without destroying normal tissue in the process.
"We are not developing a single anti-cancer therapy," says Dr. Philip S. Schein of the Lombardi Cancer Center at Georgetown University. "We are designing specific treatments for what we now recognize as over 100 different diseases."
A malignant tumor contains millions of cancer cells. Chemotherapy acts on these to destroy them or interfere with efforts to develop effective chemical therapies, researchers must harness tremendously powerful "unknown" agents with a number of possible side effects.
"Bone marrow damage has been a major limiting factor in chemotherapy," says Schein. "While a drug may act aggressively against the cancer, at the same time it commonly suppresses the function of bone marrow which produces normal blood cells vital for the body. This means treatment must be interrupted to allow the bone marrow to recover, and during this stage the cancer often recurs. Cumulative toxicity can also occur. The challenge is to improve existing therapy." To that end Schein has been working with his colleagues for almost ten years now on the development of a new drug which, it is hoped, will work against a broad spectrum of human tumors without undue destruction of bone marrow. It is called chlorozotocin and its odyssey has already run from brain-storming through research and scientific debate - in this case squabbles between the NCI and FDA - and considerable amounts of money.
Philip Schein came to cancer research almost by accident, taking up medicine after earlier experience as a concert pianist. At 38, he is an internationally recognised authority on cancer, but the zigzag part in his dark hair and persistent cowlick suggest a combination of super-scientist and Huckleberry Finn.
The story of chlorozotocin begin early in Schein's career at the National Cancer Institute. In the Sixties he was studying streptoaotocin, an antibiotic antitumor agent that is one of the "nitrisiurea" compounds. These agents were known to have generally good antitumor activity but risky bone marrow toxicity.
The research on streptozotocin led to an intersting discovery. In mice and humans the drug did not reduce normal blood counts (a sign of bone marrow damage) as most antitumor agents did. On the other hand, it did not work well against the tumors being studied.
"It was a unique situation," Schein recalls. "Could we exploit the bone-marrow-sparing property of streptozotocin and enhance its overall antitumor effect?"
To accomplish this, Schein in 1968 recommended adding a more powerful cell-killing component to the molecule - synthesizing a new glucose-containing chlorethyl nitrosourea along the lines of streptozotocin: that is, chlorozotocin. "There was no other comparable drug," he says. But often a young scientist's ideas do not carry enough weight to seem to justify the enormous price tag of developing a new drug, and initially, says Schein, there were no takers.
Later, in 1971, he again proposed synthesizing chlorozotocin, and in 1972 he conducted studies on a triscetate form of drug, but it was several months more before Dr. Tom Johnston and Dr. John Montgomery of Southern Research Institute, aware of Schein's needs, were able to produce the compound in a water-soluble form that could be injected.
"We quickly began animal testing of chlotozotcin in 1973 and found very exciting antitumor activity," says Schein. With the support of the National Cancer Institute he made further tests on the drug in animal tumors and human tissue cultures. It was shown to be effective in treatment of acute leukemia in mice. In contrast to other antitumor drugs of the same class it was also found to have relatively little toxic effect on an essential function of human bone marrow taken from volunteers. This was determined by laboratory measurements of DNA stythesis - a sign of normal bone marrow function and lack of toxicity.
Toxic features of the drug were delineated in further animal studies and a safe starting dose for human trials was estimated. Chemically, chlorozotocin was shown to be a pure, uncontaminated compound. And a suitable mode of administration in humans - injection - was proposed.
In May 1976, chlorozotocin moved ahead as the National Cancer Institute filed an application with the Food and Drug Administration for authorization as an Investigation New Drug. Permission came on July 22, 1976, allowing the first human trials to begin at the Lombardi Cancer Center under Schein.
With most drugs the first phase of human studies attempts to establish, in normal subjects, a safe and reasonable dose. Not until the second phase is there an attempt to determine therapeutic activity. But with anticancer drugs the two phases overlap. The drugs are given for the first time directly to patients with cancer and the safe and potentially effective dose levels are simultaneously sought.
Mrs. N.L. is a Phase I test patient at Georgetown's Clinical Study Unit, where she was happy to chat when she wasn't being x-rayed or undergoing a battery of tests. She had come in the day before for her third chlorozotocin treatment.
"I come every six weeks for my injection." She settled comfortable in a chair in her room to discuss the drug. "Fortunately, the medicine hasn't made me ill - just some nausea last time. I don't know if I'll get sick this time . . .
"A year ago I had surgery," she explained. "And a month later I started chemotherapy with - oh, I can't say those long names," she laughed easily behind her glasses. "They cut it off because it didn't do any good. When I had a chest X-ray, there was a spot. It had broken through. Those drugs didn't do the trick.
"My doctor said he hoped I could get into this program."
Every week, Mrs. L. has her blood tested. Routine bone marrow, liver and kidney function tests are done. The level of the drug in her blood is measured. With these tools, the researchers aim to monitor and plot out safe, yet ultimately effective doses of the drug. Usually a lowered blood count is considered the sign of a biologically effective level, but they take precautions to prevent its falling too low. Researchers walk on a thin line, flirting with the risk of infection if the white blood count becomes too low, or hemorrhage if platelets fall too far.
When a new drug is first administered, low doses are given, then gradually increased. Researchers watch for common chemotherapy side effects - nausea, vomiting, bone marrow toxicity, hair loss - as well as rigorously test for any unpredicted toxicities.
Mrs. L. has been taking it in stride. She is one of approximately 28,000 people a year in NCI-supported drug trials. Since she is on an experimental drug, she read over, discussed and finally signed an explicit permission form.. There are fifty anticancer drugs on the market today with twice that number in human cancer trials.
"These patients know where they are and what their prospects are," Dr. Dan Hoth of the Lombardi Center says. "Very few who have gotten as far as the consent form have said 'no.' They understand the chance of shrinking their tumor is a long shot, but they have used up other alternatives. In addition, some are motivated by hope that what we learn from treating them may help others.
"Here in the past year," Dr. Hoth notes, "chlorozotocin has appeared easily and well tolerated with no life-threatening toxicities. The hope is always that an effective dose is lower than a toxic one. In five patients so far we have seen definate antitumor activity."
Once a safe dose has been clearly established (with some tumor activity), the drug is released by FDA to a number of cancer centers for broader Phase 2 studies. At this point the drug could be prior therapy whose tumors may have a better chance of responding to the new agent. In Phase 3, a drug now shown to be safe and effective would be studied to find if it is any better than current established therapy. Usually the next step is to apply for a New Drug Application from the FDA. if approved, it then goes on the market as standard therapy for certain indications. Finally, a drug is studied in combination with other drugs and techniques including surgery, radiation therapy and some immunotherapy.
Under the aegis of the National Cancer Insititue, chlorozotocin is now in human or clinical trials at five centers (University of Kansas, Memorial Sloan-Kettering, and the Mayo Clinic, as well as the Lombardi Cancer Center and National Cancer Institute). At the Lombardi Center seventy patients have received chlorozotocin as an experimental anticancer drug since August 1976.
"Until the government assumed almost all of the costs, it was slow going in cancer drug development," Dr. Schein says. "The pharmaceutical companies have balked in the face of potential drug failures which would mean enormous economic losses." Thus far the National Cancer Institute has carried a tab on chlorozotocin at an estimated cost of over $200,000.
In 1977, NCI estimates spending over $125 million for anticancer drug development that includes complex preclinical and clinical testing. Last Year the FDA said they allowed seven new cancer drugs to go into human trials. Chlorozotocin was one of 15,000 compounds NCI screened that year.
As the war against cancer grows more intricate it becomes clear that no one super-drug is the answer. "The vast majority of therapy that we are using now incorporates several drugs or 'combination chemotherapy," Dr. Schein explains. "We are designing individual drug combinations that recognize the biologic features of a specific type of tumor."
This involves identifying separate drugs which have shown activity against a particular tumor and then combining them for additive effect against that type of tumor. Researchers also try to choose drugs which would not all attack the same normal tissue, so that no one organ is seriously damaged in treatment.
Perhaps chlorozotocin will be a member of such a drug combination team. But it will be years before all the results are in. Unless proven otherwise, in its complex young lifetime it remains, as Dr. Schein says, "promising." It has just gone into Phase 2.
He adds, "We are not just chemotherapists treatment tumors. We are first and foremost physicians taking into account the entire person. It's not merely a question of 'buying time' for someone. We want to maintain the quality of life at the highest level for the longest period of time.
"This is the major gameplan in cancer treatment."