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Tauromustine (TCNU) is a newly developed nitrosourea compound. As a result of molecular modification, TCNU is more hydrophilic than BCNU and CCNU. In experimental data there was a high therapeutic index, especially in Walker 256 carcinosarcoma in rats, and in phase I trials antitumor activity was observed in NSCLC (10/33 remissions). There was also activity in melanoma, breast cancer, pleuramesotheliomas and ovarian cancer. To determine the effectiveness, duration of response and toxicity of TCNU the following phase II trial was performed. Patients received 130 mg/m2 TCNU every 35 days orally. Twenty-five patients were treated; 22 were evaluable. The female/male ratio was 18/4, 1 patient was stage III, 21 patients stage IV, the mean age was 62.3 years (range 32-70). Between 1 and 4 courses (mean 1.9) were administered. Histology was as follows: 6 squamous cell, 11 adenocarcinoma, 2 large cell and 3 polymorph cell carcinomas. No objective response (CR + PR) was observed; 6/18 patients had stable disease, 7/18 progression and 5/18 early progression. The median survival time is 4.9 months. The most severe side effect was thrombocytopenia (WHO grade 3 + 4, 4/22 patients). TCNU administered at this dose and schedule does not show substantial antitumor activity in patients with NSCLC. The fact that no objective tumor remission was observed suggests that the true response rate is less than 20% (p less than 0.05). It is improbable that TCNU has a relevant impact on the course of inoperable NSCLC.

Three new nitrosoureas and chlorozotocin were screened for anticancer activity against Walker carcinoma 256 and DMBA-induced mammary cancer of the rat. High single doses (80% of LD50) of water-soluble 1-(2-chloroethyl)-1-nitroso-3-(methylencarboxamido)urea and 2-[3-(2-chloroethyl)-3-nitrosoureido]ethylmethansulfonate effected a similar tumor weight inhibition than BCNU in treatment of subcutaneously implanted Walker 256. In dose-response studies low doses of the new analogs effected a higher tumor weight inhibition than BCNU in the treatment of subcutaneously implanted Walker 256. The therapeutic index calculated as LD50/ED50, was 2.7 and 2.4 for the new compounds in comparison to BCNU with 2.1. Chlorozotocin and 1-(methylenecarboxyethyl)-1-nitroso-3-phenylurea were not active. Against DMBA-induced mammary cancer the new BCNU analogs yielded a greater tumor weight inhibition than adriamycin and BCNU. At a dose-level of approximately LD10, the remission rates of individual tumors, which were at least 0.6 g at the beginning of treatment were 46% (13/28) for therapy with 2-[3-(2-chloroethyl)-3-nitrosoureido]ethylmethanesulfonate, 32% (9/28) for 1-(2-chloroethyl)-1-nitro-3-(methylenecarboxamido)urea, 26% (6/23) for chlorozotocin, 21% (7/33) for adriamycin and 17% for BCNU, respectively. As single agents the 2 new analogs 2[3-(1-chloroethyl)-3-nitrossureido[ethylmethanesulfonate, the water-soluble 1-(2-chloroethyl)-1-nitroso-3-(methylenecarboxamido)urea and chlorozotocin were the most effective compounds against DMBA-induced mammary cancer of the rat.

CGP 6809 [ethyl-6-deoxy-3,5-di-O-methyl-6-(3-methyl-3-nitrosoureido)-alpha-D- glucofuranoside] is a new methylnitrosoureido-sugar derivative that has been shown to be active against a broad spectrum of transplantable tumours in mice and rats. We investigated the anti-tumour effect of CGP 6809 in ten selected, human tumour xenograft lines growing s.c. in nude mice. The p.o. administration of 125 mg/kg per day for 10-15 days was less toxic (lethality 12% in tumour-bearing nude mice) than the i.p. injection of 62.5 mg/kg per day (lethality 22%). The anti-tumour effect was similar for both application routes; two large bowel cancers responded to treatment with CGP 6809, rectal cancer CXF 158 showed a remission, and the rapidly growing, undifferentiated colonic cancer CXF 280 exhibited a transient no-change. Furthermore, remissions were observed in the epidermoid lung cancer LXF 322 and in thyroid cancer 117. Tumour progression was found in another epidermoid lung cancer and in three stomach cancers, one melanoma, and one soft tissue sarcoma. CGP 6809 is a promising new agent for clinical trials, especially for large bowel and epidermoid lung cancer.

N'-[N-(2-Chloroethyl)-N-nitroso]carbamoyl cysteamine (CNC-cysteamine) and several related compounds have been synthesized and tested against L 1210 leukemia in mice. Reaction of N-(2-chloroethyl)-N-nitrosocarbamoyl azide (CNC-azide) with cysteamine yielded CNC-cysteamine and bis(CNC)cystamine. Reaction of CNC-azide with cystamine in the presence of triethylamine gave bis(CNC)cystamine. Unexpectedly, formation of CNC-cystamine carboxylazide as a minor reaction product was also observed. N-(2-Chloroethyl)carbamoyl cysteamine 2-chloroethylcarbamate was formed when 2-chloroethyl isocyanate was reacted with cysteamine. Nitrosation of this cysteamine N,S-dicarbamoyl derivative led to formation of a mixture of two dinitroso isomers. Preliminary testing of the newly synthesized CNC-derivatives against L 1210 leukemia in mice revealed that CNC-cysteamine, its disulfide bis(CNC)cystamine and CNC-cystamine carboxylazide were highly active against L 1210 leukemia.

In a phase-II study 46 patients with advanced colorectal cancer were treated with the new nitrosourea ACNU [1-(2-chloroethyl)-1-nitroso-3 (4-amino-2-methyl-5-pyrimidinyl)methyl-3-nitrosourea]. From 43 evaluable patients, 86% presented distant metastases and 14% an unresectable primary tumour or a recurrent tumour. 24 patients presented a colon and 19 a rectal cancer. Prior anticancer drug treatment was given to 34 patients (79%), 11 (26%) were pretreated with a nitrosourea. ACNU was administered every 4-6 weeks as a single intravenous push injection of 100 mg/m2. Most patients received 2-3 courses. From 43 evaluable patients, one patient achieved a complete and 3 a partial remission (CR + PR 9%). 5 patients reached a minimal regression (tumour regression of less than 50%) and 5 a no change for at least 2 months. The median duration (time from beginning of ACNU therapy until tumour progression) of the 14 responders was 132 days. The median survival time was significantly longer for responders in comparison to patients with progressive disease (9.8 versus 4.1 months). The dose limiting toxicity was delayed bone marrow suppression predominantly in the form of thrombocytopenia. 22/42 patients (52%) presented a thrombocytopenia of under 50.000/mm3 with a nadir after 27 days. Leucocytopenia under 2.000/mm3 were observed in 22/40 patients (30%). A fall of haemoglobin of more than 2 g/dl was seen in 71%. Nausea or vomiting over 1-2 days were found in 59% of the treatment courses. Other drug related side effects were not encountered. ACNU has a similar activity in colorectal cancer as BCNU and CCNU.(ABSTRACT TRUNCATED AT 250 WORDS)

The newly synthesized nitrosoureas 1-(2-chloroethyl)-1-nitroso-3-(methylenecarboxamido)-urea (Acetamido-CNU), 1-(2-chloroethyl)-1-nitroso-3-(4-morpholino)-urea (Morpholino-CNU), 1-(2-chloroethyl)-1-nitroso-3-(1-piperidino)-urea (Piperidino-CNU), and 2-[3-(2-chloroethyl)-3-nitrosoureido]-ethylmethanesulfonate (Ethylmethanesulfonato-CNU) were compared in their chemotherapeutic activity against preterminal rat leukemia L 5222 with BCNU, CCNU, MeCCNU, Chlorozotocin, and Hydroxyethyl-CNU. With respect to the dose range effecting a median survival time of more than 90 days, MeCCNU was superior to the other substances. Chlorozotocin, on the other hand, was the only substance which achieved no cures in this experimental arrangement. From the four newly introduced substances the water-soluble substances Acetamido-CNU and Morpholino-CNU were approximately comparable to CCNU with regard to the dose range effecting a median survival time of greater than 90 days. Piperidino-CNU and Ethylmethanesulfonato-CNU also effected cures; however, only Piperidino-CNU in one dosage effected a median survival time of greater than 90 days.

A total of 11 newly synthesized 2-chloroethyl-nitrosoureas and 1 2-fluoroethyl-nitrosourea with short-chain substituents were tested for their cytostatic activity on the L1210 mouse leukemia in comparison to clinically used nitrosoureas. Initial experiments showed advantages of the i.v. route for tumor inoculation. Therefore, the anatomical generalisation of tumor cells after i.v. injection was studied by bio-assay. Tumor cell determinations in different organs were 10 to 100 times higher compared with i.p. implantation. Of the new compounds 10 showed marked cytostatic activity in this tumor model by producing cures, and 5 of them must be considered as superior to BCNU, the most commonly used nitrosourea.

The synthesis of new analogs of the anticancer agent BCNU is described. It involves the preparation of N-(2-chloroethyl)-N-nitrosocarbamoylazide and its reaction with aliphatic diamines and aminoalcohols to yield 1,1'-polymethylenebis 3-(2-chloroethyl)-3-nitrosoureas and 1-(omega-hydroxyalkyl)-3-(2-chloroethyl-3-nitrosoureas. Screening for chemotherapeutic activities of the newly synthesized nitrosoureas against rat leukemia L 5222 and s.c. Walker carcinosarcoma 256 revealed remarkable differences between individual compounds. The water soluble 1-(2-hydroxyethyl)-3-(2-chloroethyl)-3-nitrousourea was the most active compound of this series, effecting 90% cures in i.p. inoculated L5222 leukemia.