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Clinical cancer chemotherapy in a single institution
J. chron. Dis. Vol. 15, pp. 259-263.
CLINICAL
Pergamon Press Ltd. Printed in Great Britain
CANCER CHEMOTHERAPY SINGLE INSTITUTION*
IN A
JOHN E. ULTMANN~, ERICH HIRSCHBERG and ALFRED GELLHORN Departments of Medicine and Biochemistry, Columbia University College of Physicians and Surgeons, and the Medical Service, Francis Delafield Hospital, New York (Received
21 November 1961)
OUR group has undertaken the study of chemotherapy as one part of a number of investigations on abnormal growth. Our origin dates from the opening of the Francis Delafield Hospital in 1951 when expanded clinical facilities became available to the Cancer Research Institute of Columbia University. In a single geographic locality, a predominantly full-time staff brings together individuals with varied interests and training in clinical and laboratory disciplines to correlate observations on the wards and in the laboratory. The members of the staff, in addition to their duties related to laboratory or clinical cancer research, participate in the teaching programs of their respective During the past ten years, the staff has trained over 100 residents and an departments. equal number of medical students at the Delafield Hospital in the diagnosis and medical management of patients with neoplastic disease. One of the pleasant features of the overall program has been that it has attracted people who have stayed for long periods, and this long-term stability of professional personnel has been of tremendous advantage in our evaluation of the natural history of disease and in our appraisal of chemotherapeutic agents. Turning now to some of the specific research objectives and findings made during the last few years, four major areas may be mentioned. First, work has been going forward on a long-term basis on various aspects of cellular regulatory mechanisms in both normal and tumor tissues. This includes biochemical aspects of genetically determined enzyme deficiencies, mechanisms underlying enzyme induction and enzyme synthesis, facets of lipid biosynthesis and metabolism, intracellular organization of glucose metabolism, and pathways of amino acid metabolism. As information is acquired on these phenomena in normal cells, it is frequently applied by the same investigators to tumor cells of animal or human origin. These broad studies, often designed primarily for their own ends, at the same time may provide basic information for the eventual development of new rational approaches to chemotherapy. Second, it has long been our feeling that one of the particular contributions which internists can bring to the clinical cancer problem is a concern with the effect of *Thiswork was supported
in part by the National Cancer Institute, U.S.P.H.S. (CY-2332), the Health Research Council of the City of New York (I-109), and the Anne Winton Memorial Fund. tInvestigator, Health Research Council of the City of New York. 259
260
JOHN E. ULTMANN,
ERICH HIRSCHBERG and ALFRED GELLHORN
neoplastic disease on the physiology of the host. Clinical research by members of our group and others has improved the medical management of patients and has led to increased understanding of the mechanisms of anemia, the consequences of hypercalcemia, the disturbances of purine metabolism, the effect of overproduction or of deficiency of specific serum proteins, and the modifications of pulmonary physiology during radiotherapy. Third, the composition and orientation of our group has afforded close liaison between experimental and clinical cancer chemotherapy. The laboratory studies emphasized problems in methodology as illustrated by the collaborative evaluation of screening systems carried out by investigators in this and several other institutions in 1954, which led to the adoption of the current primary screen of sarcoma 180, carcinoma 755, and leukemia L1210 by the Cancer Chemotherapy National Service Center (CCNSC). In addition, several hundred selected compounds have been examined in a spectrum of animal tumors and in tissue culture, several of which were placed on clinical trial by members of the same group on the basis of promising laboratory findings. Two examples may be given in brief which to our mind illustrate well the function of the daily contact and collaboration which united the preclinical and clinical members of this group. Some years ago, it was postulated that there might be advantages in combining an alkylating moiety with an antimetabolite to obtain more selective antitumor compounds. This postulate led to the design of benzimidazole mustard, the open nitrogen mustard function being attached to the imidazole ring of a purine antagonist. Following its synthesis by a collaborating organic chemist, the compound underwent extensive laboratory evaluation, with the demonstration of wide effectiveness against various rodent tumors. The preclinical and clinical personnel now collaborated directly in examining the toxicology and pharmacology of the compound in larger laboratory animals and in preliminary human trial. This made it easier for the clinicians to spot the prohibitive human toxicity of this agent and to carry out and terminate the requisite clinical trial which speedily relegated it to the category of theoretically interesting but practically not usable compounds. An example with a more encouraging outcome is provided by quinacrine. The exquisitely sensitive response of brain tumor tissue cultures to this acridine dye first directed attention to its possible value in cancer chemotherapy. Despite its effects in vitro, quinacrine turned out to be essentially inactive against rodent tumors in vivo. The only exception was an ascites tumor when the drug was given by the intraperitoneal route. These findings suggested the possible application of this agent to the local treatment of neoplastic effusions in man. Prompt clinical trial followed, and the results have been generally encouraging. Effective control of recurrent effusions is achieved by instillation of quinacrine with little attendant toxicity. The question of the mechanism of this effect has again been approached by direct collaboration between clinical and preclinical members of the group, who have been able to provide evidence for the direct action of the drug on tumor cells in the effusions by the serial determination of several enzymes in these fluids during treatment. In this manner, the investigators, who comprise the chemotherapy group, undertake from a broad basis of research into the clinical chemotherapy studies biochemistry of abnormal growth, a broad view of the pathologic physiology of
Clinical Cancer Chemotherapy in a Single Institution
261
neoplastic disease, and thorough familiarity with the animal screening data and preclinical pharmacology. Lastly, in view of all these active pursuits, it may well be asked if a group such as ours has any time and energy left for the actual examination of compounds in the clinic. A brief account of the efforts of our group in this area follows. As shown in Table 1, during the ten-year period, 1951-1961, we have tested nineteen compounds in clinical chemotherapy trials. These compounds have now been tested in about 1400 patients, all observed by the same investigators. Evaluation of any one compound
TABLE 1. CLINICAL CANCER
CHEMOTHERAPY
Agent
Years employed
1952 I!a53:
I
l
TEM S~IIOlOlle
AT FRANCIS DELAFIELD H0~~1~~~(1951-1961)t
24 --
1954
I
1955
I
5 ctinoblastoma
1956
I
1957
I (art.)
* Retinobl.
- ----______ __:
I
Comment 1958
1959
1
1960
1961
*
i
50
31
I
1
--+
Sod. bicarbonate
26
6-MP
--
*-~_~--‘_ I
_-
Myerlan Sarkomycin
Urethane
-p
Drug fever
*
Hyperuricemia Leukemia program
--,.-----~ 41 *
I
Bultiple myeloma Myeloma program
Chlorambucil
Hypogammaglob., i Hemolytic anemia, [Leukemia program
Quinacrine
Neoplastic &Fusions
Amodiaquin
Glioblastoma program
Prednisone Thiotepa Benzimidazole mustard S-FU
---
--+
Melphalan
Melanoma -
Myeloma
100
>
25 Miracil D 6-Azauracil
-__t__
i
I?
Uracil mustard Cyclophosphamide
*Published
tReferen?s : TEM 11-31; Stanolone [41; 6-mercaptopurine IS]; M&ran [61; Sarkomycin [71; Chlorambucil 18, 91; Quinacnne [lo]: Prednisone [l I]; ThioTEPA [121; and Benzimidazole mustard [131.
262
JOHN E. ULTMANN, ERICH ~~SCHEJERG and ALFRED GELLHORN
from the start of the clinical trial to the date of publication of results took from two to three years and was possible after trial in from twenty-six to eight-seven patients. A very toxic compound requires a relatively small sample size to reject if for use in man. For example, Miracil D (lucanthone hydrochloride) was speedily discarded after trial in fifteen patients because of its central nervous system side effects. Similarly, we feel that an active compound does not require extensive study before it is possible to recognize its usefulness, though larger numbers of patients may be required to determine optimal dosage schedules. In the treatment of retinoblastoma with combination of radiotherapy and triethylene melamine (TEM), it became apparent after trial in twenty patients that a promising therapeutic application had been found. The subsequent enlargement of the series concerned itself mainly with determination of the optimal route of administration and dosage in these children. The experience with Myleran in chronic myeloid leukemia was essentially the same. The problem becomes most difficult in the study of agents of equivocal clinical value. In such agents, where the therapeutic reproducibility is of a low order of magnitude and toxicity uniform, even extensive, clinical trial may not be sufficient to define easily the indications and methods of treatment for the agent. 5-Fluorouracil, after a trial in 105 cases, falls into this category. Of the compounds we have tested, ten, as indicated by the arrow on the right of the table, are currently in u e in this and other medical centers. As can be seen, we rejected a number of compounds after trial in from ten to seventy-six patients, either on the basis of their toxicity or on the basis of their therapeutic inactivity. We recognize that this does not constitute an exhaustive or mathematically significant trial. However, to the best of our knowledge, results in other medical centers with six of the nine rejected compounds were also negative. Finally, this table indicates that the clinical cancer chemotherapy program has been, in many instances, part of the larger clinical program underway in our Institute, including long-term studies of the chronic leukemia% of multiple myeloma, of hyperuricemia, and hypogammaglobulinemia, of neoplastic effusions, and of glioblastoma. In conclusion, it might be emphasized that in our group cancer chemotherapy has been a part of the overall studies of the tumor-bearing host rather than a primary objective. It is our conviction that greater understanding of cancer and ultimately effective therapy will result from study of the effect of neoplastic disease on host physiology and from broad inquiry into regulating mechanisms of normal and abnormal growth rather than merely from the evaluation of a large variety and great number of potential anticancer compounds.
REFERENCES 1. 2.
GELLHORN. A., KLIGERMAN, M. M. and JAFFE, I.: Triethylene melamine in clinical cancer chemotherapy, Amer. J. Med. 13,428, 1952. HYMAN, G. A. and REESE, A. B. : Combination therapy of retinoblastoma with triethylene melamine and radiotherapy, J. Amer. med. Ass. 162, 1368, 1956.
3.
REESE, A. B., HYMAN, G. A., TAPLEY, N. DUV. and FORREST, A. W.: The treatment tinoblastoma by x-ray and triethylene melamine, A.M.A. Arch. Ophthal. 60, 897, 1958.
of re-
4.
GELLHORN, A., HOLLAND, J., HERRMANN,J. B., Moss, J. and SMELIN, A.: An evaluation of Stanolone in treatment of advanced mammary cancer, J. Amer. med. Ass. 154, 1274, 1954.
Clinical 5.
Cancer Chemotherapy
HYMAN, G. A., GELLHORN, A. and WOLFF, J. A.:
in a Single Institution
263
The therapeutic
in a
effect of mercaptopurine
variety of human neoplastic diseases, Ann. N. Y. Acud. Sci. 60,430, 1954. 6.
HYMAN, G. A. and GELLHORN, A.: Myleran therapy in malignant neoplastic disease: Use of 1,4_Dimethanesulfonyloxybutane with emphasis on chronic granulocytic leukemia, J. Amer. med. Ass. 161,844, 1956.
I.
MAGILL, G. B., GOLBEY, R. B., KARNOFSKY, D. A., BURCHENAL, J. H., STOCK, C. C., RHOADS, C. P., CRANDALL, C. E., YORUKOGLU, S. N. and GELLHORN, A.: Clinical experiences with Sarcomycin in neoplastic diseases, Cancer Rex 16,960, 1956.
8. ULTMANN, J. E., HYMAN, G. A. and GELLHORN, A.: lymphocytic
leukemia and certain lymphomas,
Chlorambucil in treatment .I. Amer. med. Ass. 162, 178, 1956.
of chronic
9.
ULTMANN, J. E., HYMAN, G. A. and GELLHORN, A.: Chlorambucil and triethylene thiophosphoramide in the treatment of neoplastic disease, Ann. N. Y. Acad. Sci. 68,1007, 1958.
10.
GELLHORN, A., ZAIDENWEBER, J., ULTMANN, J. and HIRSCHBERG, E.: The use of Atabrine (Quinacrine) in the control of recurrent neoplastic effusions, Dis. Chest 39, 165, 1961.
11.
RANNEY, H. M. and GELLHORN, A. : The effect of massive prednisone and prednisolone on acute leukemia and malignant lymphomas, Amer. J. Med. 22,405, 1957.
12.
ULTMANN, J. E., HYMAN, G. A., CRANDALL, C., NAUJOKS, H. and GELLHORN, A.: Triethylenethiophosphoramide (Thio-TEPA) in the treatment of neoplastic disease, Cancer, 10, 902, 1957.
13.
ULTMANN, J. E., THOMPSON, H. G. JR., HIRSCHBERG, E., ZAIDENWEBER, J. and GELLHORN, A.: Toxicological and clinical evaluation of a new nitrogen mustard, 2-@LX-(2-chloroethyl) aminomethyl] benzimidazole, Cancer Res. 19,719, 1959.
therapy
CLINICAL
Pergamon Press Ltd. Printed in Great Britain
CANCER CHEMOTHERAPY SINGLE INSTITUTION*
IN A
JOHN E. ULTMANN~, ERICH HIRSCHBERG and ALFRED GELLHORN Departments of Medicine and Biochemistry, Columbia University College of Physicians and Surgeons, and the Medical Service, Francis Delafield Hospital, New York (Received
21 November 1961)
OUR group has undertaken the study of chemotherapy as one part of a number of investigations on abnormal growth. Our origin dates from the opening of the Francis Delafield Hospital in 1951 when expanded clinical facilities became available to the Cancer Research Institute of Columbia University. In a single geographic locality, a predominantly full-time staff brings together individuals with varied interests and training in clinical and laboratory disciplines to correlate observations on the wards and in the laboratory. The members of the staff, in addition to their duties related to laboratory or clinical cancer research, participate in the teaching programs of their respective During the past ten years, the staff has trained over 100 residents and an departments. equal number of medical students at the Delafield Hospital in the diagnosis and medical management of patients with neoplastic disease. One of the pleasant features of the overall program has been that it has attracted people who have stayed for long periods, and this long-term stability of professional personnel has been of tremendous advantage in our evaluation of the natural history of disease and in our appraisal of chemotherapeutic agents. Turning now to some of the specific research objectives and findings made during the last few years, four major areas may be mentioned. First, work has been going forward on a long-term basis on various aspects of cellular regulatory mechanisms in both normal and tumor tissues. This includes biochemical aspects of genetically determined enzyme deficiencies, mechanisms underlying enzyme induction and enzyme synthesis, facets of lipid biosynthesis and metabolism, intracellular organization of glucose metabolism, and pathways of amino acid metabolism. As information is acquired on these phenomena in normal cells, it is frequently applied by the same investigators to tumor cells of animal or human origin. These broad studies, often designed primarily for their own ends, at the same time may provide basic information for the eventual development of new rational approaches to chemotherapy. Second, it has long been our feeling that one of the particular contributions which internists can bring to the clinical cancer problem is a concern with the effect of *Thiswork was supported
in part by the National Cancer Institute, U.S.P.H.S. (CY-2332), the Health Research Council of the City of New York (I-109), and the Anne Winton Memorial Fund. tInvestigator, Health Research Council of the City of New York. 259
260
JOHN E. ULTMANN,
ERICH HIRSCHBERG and ALFRED GELLHORN
neoplastic disease on the physiology of the host. Clinical research by members of our group and others has improved the medical management of patients and has led to increased understanding of the mechanisms of anemia, the consequences of hypercalcemia, the disturbances of purine metabolism, the effect of overproduction or of deficiency of specific serum proteins, and the modifications of pulmonary physiology during radiotherapy. Third, the composition and orientation of our group has afforded close liaison between experimental and clinical cancer chemotherapy. The laboratory studies emphasized problems in methodology as illustrated by the collaborative evaluation of screening systems carried out by investigators in this and several other institutions in 1954, which led to the adoption of the current primary screen of sarcoma 180, carcinoma 755, and leukemia L1210 by the Cancer Chemotherapy National Service Center (CCNSC). In addition, several hundred selected compounds have been examined in a spectrum of animal tumors and in tissue culture, several of which were placed on clinical trial by members of the same group on the basis of promising laboratory findings. Two examples may be given in brief which to our mind illustrate well the function of the daily contact and collaboration which united the preclinical and clinical members of this group. Some years ago, it was postulated that there might be advantages in combining an alkylating moiety with an antimetabolite to obtain more selective antitumor compounds. This postulate led to the design of benzimidazole mustard, the open nitrogen mustard function being attached to the imidazole ring of a purine antagonist. Following its synthesis by a collaborating organic chemist, the compound underwent extensive laboratory evaluation, with the demonstration of wide effectiveness against various rodent tumors. The preclinical and clinical personnel now collaborated directly in examining the toxicology and pharmacology of the compound in larger laboratory animals and in preliminary human trial. This made it easier for the clinicians to spot the prohibitive human toxicity of this agent and to carry out and terminate the requisite clinical trial which speedily relegated it to the category of theoretically interesting but practically not usable compounds. An example with a more encouraging outcome is provided by quinacrine. The exquisitely sensitive response of brain tumor tissue cultures to this acridine dye first directed attention to its possible value in cancer chemotherapy. Despite its effects in vitro, quinacrine turned out to be essentially inactive against rodent tumors in vivo. The only exception was an ascites tumor when the drug was given by the intraperitoneal route. These findings suggested the possible application of this agent to the local treatment of neoplastic effusions in man. Prompt clinical trial followed, and the results have been generally encouraging. Effective control of recurrent effusions is achieved by instillation of quinacrine with little attendant toxicity. The question of the mechanism of this effect has again been approached by direct collaboration between clinical and preclinical members of the group, who have been able to provide evidence for the direct action of the drug on tumor cells in the effusions by the serial determination of several enzymes in these fluids during treatment. In this manner, the investigators, who comprise the chemotherapy group, undertake from a broad basis of research into the clinical chemotherapy studies biochemistry of abnormal growth, a broad view of the pathologic physiology of
Clinical Cancer Chemotherapy in a Single Institution
261
neoplastic disease, and thorough familiarity with the animal screening data and preclinical pharmacology. Lastly, in view of all these active pursuits, it may well be asked if a group such as ours has any time and energy left for the actual examination of compounds in the clinic. A brief account of the efforts of our group in this area follows. As shown in Table 1, during the ten-year period, 1951-1961, we have tested nineteen compounds in clinical chemotherapy trials. These compounds have now been tested in about 1400 patients, all observed by the same investigators. Evaluation of any one compound
TABLE 1. CLINICAL CANCER
CHEMOTHERAPY
Agent
Years employed
1952 I!a53:
I
l
TEM S~IIOlOlle
AT FRANCIS DELAFIELD H0~~1~~~(1951-1961)t
24 --
1954
I
1955
I
5 ctinoblastoma
1956
I
1957
I (art.)
* Retinobl.
- ----______ __:
I
Comment 1958
1959
1
1960
1961
*
i
50
31
I
1
--+
Sod. bicarbonate
26
6-MP
--
*-~_~--‘_ I
_-
Myerlan Sarkomycin
Urethane
-p
Drug fever
*
Hyperuricemia Leukemia program
--,.-----~ 41 *
I
Bultiple myeloma Myeloma program
Chlorambucil
Hypogammaglob., i Hemolytic anemia, [Leukemia program
Quinacrine
Neoplastic &Fusions
Amodiaquin
Glioblastoma program
Prednisone Thiotepa Benzimidazole mustard S-FU
---
--+
Melphalan
Melanoma -
Myeloma
100
>
25 Miracil D 6-Azauracil
-__t__
i
I?
Uracil mustard Cyclophosphamide
*Published
tReferen?s : TEM 11-31; Stanolone [41; 6-mercaptopurine IS]; M&ran [61; Sarkomycin [71; Chlorambucil 18, 91; Quinacnne [lo]: Prednisone [l I]; ThioTEPA [121; and Benzimidazole mustard [131.
262
JOHN E. ULTMANN, ERICH ~~SCHEJERG and ALFRED GELLHORN
from the start of the clinical trial to the date of publication of results took from two to three years and was possible after trial in from twenty-six to eight-seven patients. A very toxic compound requires a relatively small sample size to reject if for use in man. For example, Miracil D (lucanthone hydrochloride) was speedily discarded after trial in fifteen patients because of its central nervous system side effects. Similarly, we feel that an active compound does not require extensive study before it is possible to recognize its usefulness, though larger numbers of patients may be required to determine optimal dosage schedules. In the treatment of retinoblastoma with combination of radiotherapy and triethylene melamine (TEM), it became apparent after trial in twenty patients that a promising therapeutic application had been found. The subsequent enlargement of the series concerned itself mainly with determination of the optimal route of administration and dosage in these children. The experience with Myleran in chronic myeloid leukemia was essentially the same. The problem becomes most difficult in the study of agents of equivocal clinical value. In such agents, where the therapeutic reproducibility is of a low order of magnitude and toxicity uniform, even extensive, clinical trial may not be sufficient to define easily the indications and methods of treatment for the agent. 5-Fluorouracil, after a trial in 105 cases, falls into this category. Of the compounds we have tested, ten, as indicated by the arrow on the right of the table, are currently in u e in this and other medical centers. As can be seen, we rejected a number of compounds after trial in from ten to seventy-six patients, either on the basis of their toxicity or on the basis of their therapeutic inactivity. We recognize that this does not constitute an exhaustive or mathematically significant trial. However, to the best of our knowledge, results in other medical centers with six of the nine rejected compounds were also negative. Finally, this table indicates that the clinical cancer chemotherapy program has been, in many instances, part of the larger clinical program underway in our Institute, including long-term studies of the chronic leukemia% of multiple myeloma, of hyperuricemia, and hypogammaglobulinemia, of neoplastic effusions, and of glioblastoma. In conclusion, it might be emphasized that in our group cancer chemotherapy has been a part of the overall studies of the tumor-bearing host rather than a primary objective. It is our conviction that greater understanding of cancer and ultimately effective therapy will result from study of the effect of neoplastic disease on host physiology and from broad inquiry into regulating mechanisms of normal and abnormal growth rather than merely from the evaluation of a large variety and great number of potential anticancer compounds.
REFERENCES 1. 2.
GELLHORN. A., KLIGERMAN, M. M. and JAFFE, I.: Triethylene melamine in clinical cancer chemotherapy, Amer. J. Med. 13,428, 1952. HYMAN, G. A. and REESE, A. B. : Combination therapy of retinoblastoma with triethylene melamine and radiotherapy, J. Amer. med. Ass. 162, 1368, 1956.
3.
REESE, A. B., HYMAN, G. A., TAPLEY, N. DUV. and FORREST, A. W.: The treatment tinoblastoma by x-ray and triethylene melamine, A.M.A. Arch. Ophthal. 60, 897, 1958.
of re-
4.
GELLHORN, A., HOLLAND, J., HERRMANN,J. B., Moss, J. and SMELIN, A.: An evaluation of Stanolone in treatment of advanced mammary cancer, J. Amer. med. Ass. 154, 1274, 1954.
Clinical 5.
Cancer Chemotherapy
HYMAN, G. A., GELLHORN, A. and WOLFF, J. A.:
in a Single Institution
263
The therapeutic
in a
effect of mercaptopurine
variety of human neoplastic diseases, Ann. N. Y. Acud. Sci. 60,430, 1954. 6.
HYMAN, G. A. and GELLHORN, A.: Myleran therapy in malignant neoplastic disease: Use of 1,4_Dimethanesulfonyloxybutane with emphasis on chronic granulocytic leukemia, J. Amer. med. Ass. 161,844, 1956.
I.
MAGILL, G. B., GOLBEY, R. B., KARNOFSKY, D. A., BURCHENAL, J. H., STOCK, C. C., RHOADS, C. P., CRANDALL, C. E., YORUKOGLU, S. N. and GELLHORN, A.: Clinical experiences with Sarcomycin in neoplastic diseases, Cancer Rex 16,960, 1956.
8. ULTMANN, J. E., HYMAN, G. A. and GELLHORN, A.: lymphocytic
leukemia and certain lymphomas,
Chlorambucil in treatment .I. Amer. med. Ass. 162, 178, 1956.
of chronic
9.
ULTMANN, J. E., HYMAN, G. A. and GELLHORN, A.: Chlorambucil and triethylene thiophosphoramide in the treatment of neoplastic disease, Ann. N. Y. Acad. Sci. 68,1007, 1958.
10.
GELLHORN, A., ZAIDENWEBER, J., ULTMANN, J. and HIRSCHBERG, E.: The use of Atabrine (Quinacrine) in the control of recurrent neoplastic effusions, Dis. Chest 39, 165, 1961.
11.
RANNEY, H. M. and GELLHORN, A. : The effect of massive prednisone and prednisolone on acute leukemia and malignant lymphomas, Amer. J. Med. 22,405, 1957.
12.
ULTMANN, J. E., HYMAN, G. A., CRANDALL, C., NAUJOKS, H. and GELLHORN, A.: Triethylenethiophosphoramide (Thio-TEPA) in the treatment of neoplastic disease, Cancer, 10, 902, 1957.
13.
ULTMANN, J. E., THOMPSON, H. G. JR., HIRSCHBERG, E., ZAIDENWEBER, J. and GELLHORN, A.: Toxicological and clinical evaluation of a new nitrogen mustard, 2-@LX-(2-chloroethyl) aminomethyl] benzimidazole, Cancer Res. 19,719, 1959.
therapy