The use of intermittent schedules of drugs to achieve selective toxicity has been called "pulsing" therapy. Such pulsing is intended to schedule the administration of a drug at such intervals as to provide a rest period for recovery of normal cells before the cancer cells multiply back to baseline. An additional example of the effectiveness of pulsing drugs in acute leukemia was found in a study in which remissions were significantly prolonged in children receiving maintenance doses of methotrexate intramuscularly twice a week, rather than orally once a day. Results of the study showed that the median duration of remission was 17 months for the former group and 3.3 months for the latter.
A technique for adjusting drug dosage to the rate of growth of the cells in a patient's tumor was reported within the past year. A mitotic count based on the rate of cell division in the tumor was taken as an indication of its growth rate.
A group of 23 patients with mycosis fun-goides, a type of malignant lymphoma, was treated with methotrexate once a week. Eight patients responded completely to this drug schedule; the others showed less response or none. When the mitotic counts of all the patients were studied, those with the lowest counts, that is, those with more slowly dividing cells, had had 100 percent response to the treatment; those with the highest counts had shown the least response. Accordingly, patients unsuccessfully treated with methotrexate on the once-a-week schedule were given the drug twice a week. Two patients who had not responded on the original schedule achieved complete remission on the new schedule.
Auxiliary, or supportive, therapy to overcome problems resulting from the disease process or drug side effects had been developed along with the drug treatment techniques. Results have been particularly effective in patients with acute leukemia, whose most serious complications are hemorrhage and infection. Hemorrhage stems from a shortage of blood platelets, and infection from a shortage of granulocytes (white cells) in the blood.
Adaptation of a plasmapheresis (plasma-removing) technique has solved the problem of obtaining the fresh platelets needed in large numbers for transfusion into patients to prevent or stop hemorrhage. Platelets and plasma are removed from whole blood by centrifugation, and the red cells promptly returned to the donor in one continuous operation. Thus, he may be able to give platelet donations as frequently as twice a week without ill effects. This type of platelet therapy, now provided in relatively few centers, will be made available in more than 30 leukemia centers throughout the country.
The transfusion of white blood cells for treatment of some infections is a more difficult problem. Antibiotics are also employed for this purpose, but in the absence of competent white cells they are often not effective.
Normal donors have few circulating white cells compared with red cells and platelets. However, the National Cancer Institute is sponsoring the development of a continuous flow blood-cell separator which is expected to produce adequate amounts of these white blood cells from normal donors. In tests of the blood-cell separator on a continuous flow basis, good yields of granulocytes have been obtained from normal human volunteers. These white cells have been found viable and suitable for transfusion into patients. Preliminary results indicate that they are effective in controlling infection in a few cancer patients.
Another approach is the development of relatively germfree treatment areas for protection of patients from infections. A continuing study of the "Life Island," a plastic bubble that encloses a bed, has shown that the incidence of infection is reduced in patients within the germ-free environment of the isolator. Maintenance of patients within the plastic bubble is a demanding, elaborate procedure for the patient and hospital staff, and assessment of the role of this technique is difficult at present.
To enlarge on the idea of the plastic isolator, development of laminar-flow rooms is in progress. In such rooms, visitors entering downwind will not infect a patient with bacteria because contaminated air is blown into filters and rendered germfree before it is recirculated to him.
An area of major research effort in cancer chemotherapy is the search for new drugs. Ideally, such research requires accurate systems for prediction of therapeutic effectiveness of candidate compounds in patients and for prediction of toxicity, and a knowledge of the relation of chemical structure to anticancer activity and toxicity. While none of these conditions has been fully met, the National Cancer Institute's comprehensive cancer chemotherapy program, in operation since 1955, has produced enough quantitative data in animals and patients to permit increasingly sophisticated approaches to the identification and characterization of effective agents.
Critical to the search for new cancer drugs is the primary screen, which yearly selects for further testing about 15 compounds from some 15,000 new synthetic and natural materials. The primary screen for the past several years has consisted of two laboratory animal systems: L1210 leukemia in the mouse and Walker 256 in the rat. Research on improving the predictive ability of the primary screen is a continuing process. For example, consideration is being given to removing Walker 256 temporarily from the screen, since it has not been yielding as broad a spectrum of agents as desirable. Other laboratory animal systems being evaluated include P-388 leukemia, which is sensitive to several materials of potential interest, particularly an antibiotic, mithramycin; and spontaneous AKR leukemia.
Of the 15,000 agents screened each year, half may be synthetic chemicals, including hormonal compounds, and the other half, fermentation products and plant and animal products. Although natural products represent a source of high potential, few have been tested in the primary screen. As a consequence, interest is focusing on obtaining extracts from algae and other marine plants, and from animals, insects, and higher plants from different geographical areas, as well as pure materials already isolated from natural products by investigators throughout the world.
Concurrently, studies attempting to relate chemical structures to anticancer activity are in progress. It is hoped that in the future structure-function considerations will play a greater role in determining the compounds to be introduced into the screen. These compounds would include some in which the molecule of natural products was altered, and new synthetic structures designed for producing anticancer activity.
Another element in the screening process concerns the prediction, on the basis of animal studies, of the quality and severity of toxic effects that can be expected to attend clinical use of new drugs. Because of precise data available from animal studies and better understanding of the correlation of such information with clinical results, prediction of starting doses of new drugs has been made increasingly reliable.
Expanded pharmacologic studies of active drugs, comparing the disposition of the drugs in animals and man, have yielded important new knowledge in the past year. Cyclophosphamide, one of the drugs studied, is an excellent cancer drug in animal systems but, although a very good drug in clinical cancer, its performance falls short of the animal model. Studies showed that unaltered cyclophosphamide is essentially inactive as an antitumor agent. The metabolites are the active compounds; they are present in high concentrations in the mouse and rat, but in low concentrations in patients. Further studies of the active metabolites are in progress.
A number of new materials have progressed recently to preclinical toxicological studies or toward clinical trials. Among these was a compound, Lapachol, which had a high degree of activity in the Walker 256 screen. The substance is a pigment derived from the heartwood of the so-called lapacho tree and related species, and is structurally related to vitamin K. It has been prepared for initial clinical trial.
Among other agents of potential usefulness receiving consideration in clinical trials is L-asparaginase. This compound, an enzyme found in animal tissues and bacteria, exerts its antitumor activity by breaking down the amino acid, L-asparagine. Studies reported this year indicated that mouse leukemic cells that are destroyed by asparaginase lack an enzyme, asparagine synthetase, which is known to be involved in the manufacture of asparagine. However, those leukemic cells that are resistant to asparaginase and also normal cells have high levels of the enzyme, synthetase. The lack of asparagine synthetase by certain cells makes them dependent on obtaining asparagine from an external source, such as the blood. Normal cells and cells of nonresponsive tumors do not require an external source of asparagine.
Clinical trials of L-asparaginase are being conducted in patients with acute leukemia and lymphosarcoma. Tests in the test tube indicating dependence on asparagine have been capable of distinguishing patients who would respond to L-asparaginase. Results in some patients are encouraging, but thorough evaluation of L-asparaginase will probably require some years of investigation.
The progress made in drug research has added a factor of confidence in ultimate success to the hope that existed a quarter of a century ago. Research leads such as those described in this report appear to have the potential for yielding increasingly better control of human cancer with drugs. Pursuit of such leads, derived more and more frequently from truly quantitative laboratory and clinical investigations, offers opportunity for effective use of the available resources for cancer chemotherapy research.