Hormones are used to attempt to create a hormonal environment in a patient which will cause regression of his cancer. Male and female sex hormones and hormones such as cortisone are useful as cancer drugs. Two plant alkaloids, vinblastine and vincristine, derived from the periwinkle plant, appear not to interfere with DNA synthesis but to block division of the cell.

Antibiotics have yielded effective cancer drugs: dactinomycin, isolated from a soil fungus of the genus, Streptomyces, and daunomycin, extracted also from a species of Streptomyces. Other relatively new drugs whose mechanisms of action are still uncertain are methyl GAG (methylglyoxal-bis-guanylhydrazone) and methyl hydrazine derivative.

An area of intense research interest in the past several years is cell kinetics, in which growth characteristics of populations of cancer and normal cells are being investigated and the relative effects of cancer drugs on them determined. With such information, investigators will be increasingly able to measure the effectiveness of drug therapy and to alter or devise techniques for improving it.

Estimates have suggested that leukemic cells double in number on an average of every 4 days and that the size of the cell population that kills an individual is one trillion (10^12). Other calculations have suggested that the best therapies today can reduce the lymphocytic leukemic cell population to one million (10^6). The goal of chemotherapy, then, is to eliminate the last million leukemic cells, since scientists, in general, assume that every leukemic cell must be destroyed to achieve cure.

With present techniques, however, the number of cells ordinarily cannot be measured below the level of one billion (10^9). At this point a patient can be in complete remission, that is, blood and bone marrow considered normal and all evidence of disease absent. The number of cells present can be determined only indirectly by the duration of remission without maintenance drug treatment. Hence, an urgent problem under investigation is to devise quantitative methods for measuring the number of cancer cells remaining after treatment.

For effective treatment, the percentage of the cell population killed by a drug must be high enough so that multiplication of surviving cancer cells will not outpace the inhibiting effect of the drug. Laboratory studies have shown that a given dose of a drug kills the same percentage of leukemia cells, regardless of the size of the cell population. For example, the same dose of a drug may kill 99 percent of 100,000 or 99 percent of 1,000,000 leukemic cells.

Another finding is that, with single doses of drugs, the higher the dosage the greater the percentage kill of leukemia cells. A third finding relates to the importance of spacing the administration of a drug as a means of killing a large percentage of tumor cells.

Recent studies have indicated that increased doses of some drugs can destroy larger fractions of cancer cells without greater toxicity to normal cells. Evidence has suggested, for example, that a certain percentage of normal bone marrow stem cells (the most primitive cells in the bone marrow) is in a nondividing stage when some drugs do not affect them. Lymphoma cells, however, seem not to have such a phase and are therefore more susceptible to the toxic effects of the drugs.

Other evidence has indicated, in addition, that some drugs kill cells only in one stage of their division cycle, and that different drugs attack different stages of the cell division cycle. Thus, alkylating agents act on cells in all phases of the division cycle, and also act on some resting cells. Antimetabolites attack cells only in the phase in which DNA is being synthesized and do not act on resting cells. Vincristine seems to act after the DNA synthesis phase but before the cell divides.

Laboratory studies are being focused with increasingly greater intensity on the kinetics of the growth of solid tumors to provide basic information for improved schedules of drug treatment. One of the findings is that as a tumor grows larger the time it takes for its volume to double becomes longer and longer. The time required for one tumor cell and its progeny to multiply to the estimated lethal number of one trillion may be measured in years.

Among the questions as yet unanswered about solid tumors is the reason for their long doubling time as they get older. One suggested explanation is that cells may begin to crowd together and that a certain fraction may stop dividing. Studies of slowly growing tumors in animals using radioactive-labeled compounds have shown that only about one percent of the tumor cells were proliferating. The slowdown in proliferation may be due to decreased availability of nutrients or oxygen.

Another question relates to the measurement of the response of a solid tumor to treatment. Diameter, volume, and weight are not satisfactory end points, since the size of a tumor seems to be related to the relative percentages of viable and dividing cells and of dead and dying cells. Sometimes, after cells have been exposed to a lethal dose of a drug, they can go through one more division cycle and actually show an increase in volume, before the tumor decreases in volume and then regrowth begins.

Results of the studies of cell kinetics of rapidly growing tumors have led to substantial improvement in the treatment of patients with diseases such as acute leukemia, choriocarcinoma, and some childhood tumors. An example of an effective treatment program is one in progress at the National Cancer Institute for the treatment of children with acute lymphocytic leukemia.

In the study, massive doses of four drugs, vincristine, prednisolone, 6-mercaptopurine, and methotrexate, were given in an intermittent schedule for up to 14 months. At the start of therapy, the regimen consisted of 5-day courses of drug infusion, separated by drug-free intervals of 5 to 10 days depending upon toxicity encountered. Four additional courses were given during the first two months of remission, and then 12 additional maintenance courses at monthly intervals. Supportive therapy with platelet transfusions and antibiotics was given throughout the course of treatment as needed.

Thirty-two of the 35 patients in this study (91 percent) achieved a complete remission within a period averaging 22 days. The median duration of this remission was 13 1/2 months, almost twice as long as was achieved in Institute studies in which drug combinations were given in smaller doses for shorter periods. Sixteen children are surviving for periods up to 3 years and 2 months following the start of therapy. The median survival time of the 35 patients in this study is about 3 years.