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.

Another compound, dimethyl triazeno imidazole carboxamide, is being tried cautiously in initial clinical trials,after itshowed a high degree of activity against mouse leukemia L1210 and received extensive studies in animals.

lapacho tree

The heartwood of the lapacho tree and related species has yielded a compound, Lapachol, which in preliminary studies has shown a high degree of anticancer activity in the laboratory animal screen. It has been prepared for initial clinical trial.

Among other agents, not previously mentioned in this report, which are receiving consideration in clinical trial, is L-asparaginase.

This compound, an enzyme found in animal tissues and bacteria, some years ago showed activity against some mouse leukemias and other experimental tumors.

The cells of such responsive tumors require for growth the amino acid, L-asparagine, from an external source, such as the blood; normal cells and cells of nonresponsive tumors do not require an external source of this amino acid. Asparaginase exerts its antitumor activity by breaking down the amino acid 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, the 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, which makes these cells dependent on-an external source of asparagine, is thus a clearly defined qualitative biochemical difference between normal and cancer cells.

Clinical trials of this material are being conducted in patients with acute lymphocytic leukemia, acute granulocytic leukemia, and lymphosarcoma. Tests in the test tube indicating dependence on asparagine have been capable of distinguishing patients who would respond to asparaginase. Results in some patients are encouraging, but some years will elapse before the true efficacy of L-asparaginase as a cancer drug is known.

Another relatively new agent is dibromoman-nitol, a drug developed in Europe for the treatment of adults with chronic granulocytic leukemia. A clinical trial has shown activity of the drug, with few toxic side effects. The percentage of patients responding to treatment compared favorably with the response expected following treatment with Myleran (busulfan), the drug most frequently prescribed for patients with this disease.

Conclusion

It might seem almost as if in the past quarter of a century the search for curative drugs for cancer had traveled a complete cycle: then, as now, investigators were seeking chemical compounds that would destroy malignant disease anywhere in the body without harm to the patient. The differences in the intellectual approaches and the useful techniques, then and now, are a measure of the progress made toward the goal. Too, a factor of confidence in ultimate success, based on sound scientific principles and proved experimental and clinical procedures, has been added to the hope that existed 25 years ago.

Complete remissions for extended periods are now readily produced in patients with diseases such as acute leukemia, Burkitt's tumor, and Wilms' tumor, at present recognized as rapidly growing tumors. Use of intermittent schedules of intensive combination drug therapy results in predictable remissions in a high percentage of patients. An important need is to learn how to consistently prolong the durations of remission so that in the years to come attainment of cure will be a regular rather than occasional result of treatment. Vital to the fullest expression of this scientific goal is the need to adapt and extend the complex treatments now available to patients at the major research centers to those in average hospitals in the United States, so that all patients will have equal prospects for long-term survival.

In terms of response to drug treatment, the difference between the rapidly growing tumors and the ones with slower growth rates, that is, solid tumors such as those of the breast, lung, and colon, may be explainable on the basis of the percentage of tumor cells in proliferation. It appears that only a very small percentage of cells of slowly growing tumors is proliferating and therefore selectively susceptible to attack by drugs. This difference suggests a basis for studies of reoriented drug regimens, since those designed to control tumors in which more than 80 percent of the cells are in proliferation can hardly be expected to control tumors with only a few percent of the cells proliferating. This is an area of intense research exploration at the present time. Several important leads have been developed in experimental models and need to be investigated in clinical trials.

Finally, studies of pharmacological disposition of antitumor drugs in the body need to be expanded. Improved correlations between drug effects in animals and man lead to increasing confidence in the ability of animal studies to predict safe dosage and possible side effects in patients. In addition, such studies reveal the drug metabolites that are essential for antitumor activity and point the way to precise design and synthesis of effective agents. 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 offers opportunity for the most direct and effective use of the available resources for cancer chemotherapy research.