Treatment of acute leukemia in children with and without folic acid antagonists

1952 ◽  
Vol 41 (4) ◽  
pp. 377-394 ◽  
Author(s):  
H.G. Poncher ◽  
H.A. Waisman ◽  
J.B. Richmond ◽  
O.A. Horak ◽  
L.R. Limarzi
Keyword(s):  
Folic Acid ◽  
Acute Leukemia ◽  
Folic Acid Antagonists ◽  
Leukemia In Children

OBSERVATIONS ON ACUTE LEUKEMIA IN CHILDREN TREATED WITH 4-AMINOPTEROYLGLUTAMIC ACID

PEDIATRICS ◽  
1950 ◽  
Vol 5 (1) ◽  
pp. 52-56
Author(s):  
STEPHEN D. MILLS ◽  
J. M. STICKNEY ◽  
ALBERT B. HAGEDORN
Keyword(s):  
Folic Acid ◽  
Acute Leukemia ◽  
Fatal Disease ◽  
Toxic Agent ◽  
Pharmaceutical Firms ◽  
Research Division ◽  
Folic Acid Antagonists ◽  
Widespread Interest ◽  
Fourth Position ◽  
Leukemia In Children

THE RECENT publications of Farber and co-workers dealing with the treatment of acute leukemia in children have awakened widespread interest. Their investigations have stimulated hope for the amelioration of symptoms of this fatal disease and indicated the possibility of provoking remissions that lengthen the lives of those patients affected by it, while making them more comfortable at the same time. In investigating leukemia and allied conditions of a neoplastic nature, Farber and co-workers noted what they termed an "acceleration phenomenon" in the blood and bone marrow of leukemic children treated with folic acid or its conjugates such as diopterin (pteroyldiglutamic acid) or teropterin (pteroyltriglutamic acid). There was marked hyperplasia of the marrow as well as of other sites of leukemic involvement at postmortem examination. They reasoned that if folic acid or its conjugates speeded up the leukemic process, an antagonist to folic acid might be devised in order to retard the progress of the disease or stop it altogether. Through co-operation with the research division of one of the major pharmaceutical firms, a series of folic acid antagonists was soon developed. One of these was aminopterin (4-aminopteroylglutamic acid). It differs from folic acid only in the substitution of the NH2 group for the OH radical in the fourth position of the pteridine group. Of several compounds synthetically made, it has been the most effective and yet most toxic agent in its action on the leukemic process. Farber and co-workers first employed aminopterin in the treatment of acute leukemia of children in December 1947.

SOME OBSERVATIONS ON THE EFFECT OF FOLIC ACID ANTAGONISTS ON ACUTE LEUKEMIA AND OTHER FORMS OF INCURABLE CANCER

Blood ◽  
1949 ◽  
Vol 4 (2) ◽  
pp. 160-167 ◽  
Author(s):  
SIDNEY FARBER
Keyword(s):  
Folic Acid ◽  
Acute Leukemia ◽  
Incurable Cancer ◽  
Antagonist Therapy ◽  
Initial Report ◽  
Toxic Compounds ◽  
Folic Acid Antagonists ◽  
Number Of Patients ◽  
Related Compounds ◽  
Leukemia In Children

Abstract A general discussion is presented of the present status of folic acid antagonist therapy in acute leukemia in children and in other forms of incurable cancer. Conclusions reached in our initial report have been supported by a far greater experience. Temporary remissions in acute leukemia as marked as those caused by aminopterin have been produced by the use of two compounds closely related chemically to aminopterin—amethopterin and amino-an-fol, both of which, however, are also toxic compounds. Despite the increasing number of patients in whom temporary remissions have been produced, with survival in some far beyond the usual course of the disease, no evidence has been presented which would justify the use of the word "cure" of acute leukemia. A carcinolytic action on related and on certain unrelated forms of incurable cancer has been observed. Further research for less toxic related compounds with even greater effectiveness is not only justified by these studies but is imperative. The value of this direction of research in cancer has been established. Two of the most pressing problems demanding solution are concerned with the nature, the prevention, and the treatment of toxic changes, including hemorrhage, produced by these folic acid antagonists and the causes, prevention and mechanism of hemorrhage in acute leukemia. The use of the folic acid antagonists in the treatment of incurable cancer including leukemia must remain in the realm of research until answers to these questions are found.

scholarly journals The effects of the folic acid antagonists and 2,6-diaminopurine on neoplastic disease.With special reference to acute leukemia

Cancer ◽  
1951 ◽  
Vol 4 (3) ◽  
pp. 549-569 ◽  
Author(s):  
Joseph H. Burchenal ◽  
David A. Karnofsky ◽  
Elizabeth M. Kingsley-Pillers ◽  
Chester M. Southam ◽  
W. P. Laird Myers ◽  
...  
Keyword(s):  
Folic Acid ◽  
Acute Leukemia ◽  
Special Reference ◽  
Folic Acid Antagonists

scholarly journals The Effectiveness of Combinations of Antileukemic Agents in Inducing and Maintaining Remission in Children with Acute Leukemia

Blood ◽  
1965 ◽  
Vol 26 (5) ◽  
pp. 642-656 ◽  
Author(s):  
EMIL FREI ◽  
MYRON KARON ◽  
ROBERT H. LEVIN ◽  
EMIL J. FREIREICH ◽  
ROBERT J. TAYLOR ◽  
...  
Keyword(s):  
Folic Acid ◽  
Complete Remission ◽  
Acute Leukemia ◽  
Acute Lymphocytic Leukemia ◽  
Chemotherapeutic Agents ◽  
Lymphocytic Leukemia ◽  
Folic Acid Antagonists ◽  
Remission Rates ◽  
Additive Increase ◽  
Meningeal Leukemia

Abstract 1. Combinations of effective agents produce at least an additive increase in complete remission rates over that which can be achieved when the agents are used individually. 2. Patients who do not achieve complete remission with initial treatment have a significantly shorter survival. 3. Alternating MTX and 6-MP at 28-day intervals during remission does not prolong the duration of remission over that of combined concurrent 6-MP and MTX. 4. The administration of folic acid antagonists intrathecally at 28-day intervals during antimetabolite maintained remission did not prolong the duration of remission. Meningeal leukemia, however, occurred significantly less frequently in these patients. 5. The duration of combined 6-MP and MTX maintained remission is not greater than that of 6-MP maintained remission. 6. The toxicity of 6-MP and MTX in combination in patients in remission is additive. The above conclusions were drawn from this comparative study of combinations of chemotherapeutic agents in children with acute lymphocytic leukemia.

scholarly journals Clinical Evaluation of a New Antimetabolite, 6-Mercaptopurine, in the Treatment of Leukemia and Allied Diseases

Blood ◽  
1953 ◽  
Vol 8 (11) ◽  
pp. 965-999 ◽  
Author(s):  
J. H. BURCHENAL ◽  
M. L. MURPHY ◽  
R. R. ELLISON ◽  
M. P. SYKES ◽  
T. C. TAN ◽  
...  
Keyword(s):  
Folic Acid ◽  
Acute Leukemia ◽  
Clinical Improvement ◽  
Gastrointestinal Symptoms ◽  
Practical Interest ◽  
Cross Resistance ◽  
Hematologic Toxicity ◽  
Acute Leukemias ◽  
Myelocytic Leukemia ◽  
Folic Acid Antagonists

Abstract 1. A new antimetabolite, 6-mercaptopurine, has been shown to produce good clinical and hematologic remissions in fifteen out of forty-five children with acute leukemia. Another ten showed partial remissions and clinical improvement. 2. Remissions in adults with acute leukemia have occasionally been brought about by 6-mercaptopurine, and in a few cases it has produced temporary remissions in both the early and the late stages of chronic myelocytic leukemia. 3. The compound has been effective in some children whose disease was resistant to the folic acid antagonists, as shown by the fact that out of twenty-four children with acute leukemia whose disease had been proved to be resistant to amethopterin, five had good clinical and hematologic remissions and five had partial remissions with some marrow and clinical improvement. Some benefit was seen in eight out of eighteen patients whose disease was resistant to ACTH and cortisone. 4. In children the daily oral administration of 2.5 mg./Kg. rarely caused toxic manifestations, but continued therapy at this dose in adults or at higher levels in children occasionally produced bone marrow depression or gastrointestinal symptoms. 5. There is evidence that the therapeutic resistance of the acute leukemias to 6MP develops somewhat more rapidly than it does to the folic acid antagonists but there is, as yet, no laboratory or clinical evidence of cross resistance between these two types of antimetabolites. 6. In a total of thirty-five patients with lymphomas and miscellaneous carcinomas and sarcomas, 6MP did not produce any definite clinical improvement at doses which produced hematologic toxicity. 7. Although 6-mercaptopurine acts as a purine antagonist in certain forms of bacteria, the exact mechanism of its action in leukemia is at present unknown. Since its mode of action appears to differ from that of other agents previously employed clinically in the treatment of leukemia, this compound would appear to be of fundamental as well as practical interest.

scholarly journals Observations on the Effect of Various Folic Acid Antagonists on Acute Leukemia

Blood ◽  
1951 ◽  
Vol 6 (11) ◽  
pp. 1002-1012 ◽  
Author(s):  
SLOAN J. WILSON
Keyword(s):  
Folic Acid ◽  
Acute Leukemia ◽  
Leukemic Cells ◽  
Acute Monocytic Leukemia ◽  
Acute Lymphatic Leukemia ◽  
Older Individuals ◽  
Monocytic Leukemia ◽  
Toxic Reaction ◽  
Lymphatic Leukemia ◽  
Folic Acid Antagonists

Abstract 1. Seventy patients with acute leukemia were treated with various folic acid antagonists. Sixty-five survived for a sufficient length of time to evaluate the effect of the therapeutic agents. Types of leukemia observed included 38 cases of acute lymphatic leukemia, 23 patients with acute monocytic leukemia and 4 with the acute myelogenous type of leukemia. 2. The best results, both clinically and hematologically, were obtained in acute lymphatic leukemia. Although the most satisfactory results were observed in the youngest age group, excellent remissions were produced in older individuals. Of 65 cases observed, an excellent clinical and hematologic remission was observed in 11 patients, a partial emission in 19 subjects, and no response in 35 individuals. 3. When a response occurred, a rater definite hematologic pattern was noted. An increased platelet count in most instances was the first evidence of regeneration and occurred in about the third or fourth week. The neutrophilic polymorphonuclear leukocytes began to regenerate at about the same time and an increase in their number was followed by a rise in the erythrocyte count. 4. Observations of the bone marrow indicated that although excellent clinical and hematologic remissions might occur, primitive leukemic cells were still present. In some instances megaloblasts were observed in addition to a peripheral macrocytosis and anisocytosis of erythrocytes. 5. Toxic manifestations were common. These included glossitis, ulceration of the oral cavity, nausea, vomiting, diarrhea and alopecia. In one instance there was ulceration of the entire gastro-intestinal tract, including the esophagus and colon. Hematologic toxic reactions included thrombocytopenia, leukopenia and anemia. Aplasia of marrow tissue was observed in 1 instance. In many instances the margin of safety between a toxic reaction and death was indeed small. 6. It should be emphasized that in no instance has a cure of leukemia resulted from treatment with a folic acid antagonist although prolonged remissions have occurred.

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