Experimental and clinical effect of ACNU in Japan, with emphasis on small-cell carcinoma of the lung

Abstract

The experimental and clinical effects of ACNU so far recorded in Japan are reviewed. ACNU was highly effective in leukemia L-1210 and in other types of leukemias, ascites tumors, and solid tumors of mice and rats. On the basis of the results of phase I study, the maximum clinically tolerable single dose of ACNU was 101.8-135.7 mg/m2 at a time, and the total acceptable dose was 300-600 mg. The desirable interval between doses was 6-8 weeks. Phase II study revealed that ACNU seemed to be effective against small-cell carcinoma of the lung, brain tumors, Hodgkin's disease, and chronic myelocytic leukemia. In the treatment of small-cell carcinoma of the lung ACNU reduced the rate of brain metastasis and prolonged the survival of patients.

Phase II study of ACNU in non-small-cell lung cancer: EORTC study 08872

“…Using a slightly lower dose, Sasaki et al [4] observed no responders among 21 patients. The better results of Saijo and Niitani [3] cannot be explained by selection of histology. In our study, only 1 of 29 patients with squamous-cell carcinoma responded.…”

“…Apart from bone marrow toxicity, ACNU produces only minor gastrointestinal side effects; it lacks nephrotoxicity and pulmonary toxicity, in contrast to methyl-CCNU and BCNU. Because of these characteristics and the response rate of 17.8% previously observed in squamous-cell lung cancer [3], our group considered it worthwhile to study ACNU in all histological subtypes of lung cancer. On the schedule used in the present study, we could not verify the results obtained by Saijo and Niitani [3]; we observed 1 complete and 2 partial responses in 50 evaluable patients.…”

“…Because of these characteristics and the response rate of 17.8% previously observed in squamous-cell lung cancer [3], our group considered it worthwhile to study ACNU in all histological subtypes of lung cancer. On the schedule used in the present study, we could not verify the results obtained by Saijo and Niitani [3]; we observed 1 complete and 2 partial responses in 50 evaluable patients. Using a slightly lower dose, Sasaki et al [4] observed no responders among 21 patients.…”

“…The experience with A C N U in non-small-cell lung cancer is very limited. In a phase II study performed by Saijo and Niitani [3], a response was observed in 5 of 28 patients (17.9%) with squamous-cell carcinoma of the lung. To confirm these results and to augment the current experience with A C N U in non-small-cell lung cancer, the E O R T C Lung Cancer Cooperative Group decided to perform a phase II study of A C N U in non-small-cell lung cancer.…”

Carcinogenicity of 1-(4-Amino-2-Methylpyrimidine-5-yl)-Methyl-3-(2-Chloroethyl)-3-Nitrosoureahydrochloride and Three Related N-Nitroso Derivatives following Repeated Intravenous Administration to Male Wistar Rats

“…This activity, however, was not ob served in most clinical studies [3,18]. Moreover, their use is limited by their hematologic toxicity which be comes cumulative with repeated doses [3], To overcome the disadvantages of clinically used CNUs of the first generation [HECNU]); these drugs show some anti neoplastic activity against brain tumors, lymphomas, small cell lung cancer, melanoma and neoplasms of the gastrointestinal tract [3,8,9,15,20]. Further development is directed towards increased specificity and decreased systemic toxicity by linking the active nitrosoureido-group to suited carriers, such as hor mones or peptides [2,21], A further disadvantage of presently used CNUs is the possible induction of second malignancies, which was first described in animals [11,12,23] and later in man, too [10][11][12]17].…”