Nitrosourea Research Articles

ChemInform Abstract: Formation of Novel 1,2‐Oxathietanes from 2‐Chloroethyl Sulfoxide Precursors and Their Reactions in Solution, Including Formal [σ2s + σ2a] Cycloreversions and Rearrangements.

AbstractSpontaneous decomposition of the antileukemic nitroso urea (Ia) and its alkyl‐substituted analogues (Ib)‐(Id) (the preparation of which is described) affords fragmentation products (III)‐(IX) through the intermediacy of novel 1,2‐oxathietanes (II).

Carbamoylation, inhibition of glutathione reductase and chemopotentiation of nitrosoureas by misonidazole

Experiments were designed to determine whether carbamoylation-related inhibition of glutathione reductase (GR) was involved in the previously reported correlation between nitrosourea carbamoylating activity (defined by the extent of binding to L-lysine) and the magnitude of Misonidazole (MISO) chemopotentiation. The extent to which 12 different nitrosoureas (NUs) inhibited GR activity in extracts of EMT-6/Ro cells was determined and compared to the magnitude of chemopotentiation realized when each was combined with MISO for the treatment of EMT6/Ro cells in vitro. No correlation was observed between glutathione reductase inhibition and the potentiation of nitrosourea cytotoxicity by MISO in vitro, suggesting that inhibition of GR was not involved in the mechanism of MISO chemopotentiation. Furthermore, when the original correlation was re-examined with the inclusion of additional chemopotentiation data for four hydroxylated analogs of CCNU, including two which possess little or no lysine-carbamoyladng activity but which were significantly enhanced by MISO, a correlation between carbamoylation and the magnitude of MISO chemopotentiation could not be established. From these studies we conclude that NU-carbamoylating activity is not the prime determinant of interaction between MISO and the NUs.

Reduction of pulmonary metastases of B16 melanoma by human recombinant interleukin 2 and lymphokine-activated killer cells in immunosuppressed C57BL/6 mice receiving anticancer agent.

The immunosuppressive effect of a water-soluble nitrosourea derivative, 1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU), was evaluated in terms of the cytotoxicity of spleen lymphocytes, and the restoring effect of lymphokine-activated killer (LAK) cells and/or human recombinant interleukin-2 (rIL-2) on the cytotoxicities of spleen lymphocytes was examined in ACNU-treated C57BL/6 mice. In addition, we tested whether the administration of LAK cells and/or rIL-2 could reduce the increased numbers of pulmonary metastases in ACNU-treated mice. The maximum effective dose of ACNU suppressed the cytotoxicity of spleen lymphocytes and pretreatment with ACNU enhanced the induction of artificial pulmonary metastases. The administration of LAK cells and/or human rIL-2 restored the cytotoxicity of spleen lymphocytes against YAC-1 and syngeneic B-16 melanoma cells in ACNU-treated mice, and these treatments partially suppressed the increased numbers of artificial pulmonary metastases of B-16 melanoma cells in ACNU-treated mice. These results are extremely important in providing a rationale for the introduction of adoptive immunotherapy using LAK cells and rIL-2 in patients with advanced cancer who are being treated with anticancer agent(s).

Toxicological study on a new nitrosourea derivative, 1-(2-chloroethyl)-3-isobutyl-3-(beta-maltosyl)-1-nitrosourea.

TA-077, 1-(2-chloroethyl)-3-isobutyl-3-(beta-maltosyl)-1-nitrosourea, is a new water-soluble nitrosourea derivative which is disubstituted at the N-3 position of the structure, and is activated by a unique mechanism whereby organic isocyanates can never be produced. In order to clarify the biological functions of the organic isocyanates which common nitrosourea derivatives generate, TA-077 was tested in BDF1 mice for lethality, weight loss and hematological toxicity. TA-077 showed qualitatively and quantitatively similar toxicity to other nitrosourea derivatives which generate organic isocyanates, such as 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitrosour ea (ACNU), methyl 6-[3-(2-chloroethyl)-3-nitrosoureido ]-6-deoxy-alpha-D-glucopyranoside (MCNU), and 1-(2-chloroethyl)-3-(beta-D-glucopyranosyl)-1-nitrosourea (GANU), indicating that the organic isocyanates do not play an important role in the biological activity of the nitrosourea derivatives. Furthermore, the toxicity of TA-077 did not increase significantly (except for weight loss) when the drug was administered daily for five days, and TA-077 given according to this schedule showed far more effective antitumor activity than when given as a single treatment. These results suggested that TA-077 is an analog suitable for consecutive administration in cancer treatment.

Potentiation by squalene of antitumor effect of 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-nitros ourea in a murine tumor system.

The effect of squalene (SQ) on the antitumor activity of 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitros our ea (ACNU) was studied in a murine tumor system. SQ at 4.2 g/kg exhibited a significant potentiating effect on the activity of 10 mg/kg of ACNU against lymphocytic leukemia P388 and resulted in some long-term survivors without toxicity to the host. Simultaneous administration of SQ and ACNU was most effective.

Synthesis and antitumorigenic activity of L-lysine nitrosocarbamates

After the high antitumorigenic activity of nitrosourea derivatives has been established on many experimental tumors, research on their structural analogs developed. Nitroso derivatives of alkylbiurets, alkylureas, carboxamides, alkylnitroguanidines, and alkylthioureas were obtained [I, 2]. In continuation of these studies, we synthesized nitrosocarbamates (Ia, b) in which the residue of the natural amino acid L-lysine (II) is the carrier of the cytotoxic nitrosocarbamate grouping.

Rapid induction of carcinoma in situ in dog urinary bladder by sequential treatment with N-methyl-N'-nitrosourea and N-butyl-N-(4-hydroxybutyl)-nitrosamine.

A highly atypical intraepithelial proliferation, which was interpreted as carcinoma in situ, developed in the urinary bladder of 2 beagle dogs after repeated intravesical instillations of N-methyl-N'-nitrosourea followed by oral administration of N-butyl-N-(4-hydroxybutyl)nitrosamine. The latent period was 37 weeks. The technique may provide a useful model to study the natural history of bladder cancer, particularly carcinoma in situ.

Sensitivity difference of rat ascites hepatoma AH-13 and mouse leukemia L-1210 to nitrosourea derivatives.

The structure-activity relationship in different sensitivity of AH-13 and L-1210 to nitrosourea nad related derivatives was examined. N-Methyl-N-nitrosoureido derivatives, such as 1-methyl-1-nitrosourea (MNU) and 1, 1'-polymethylene-bis(3-substituted 3-nitrosourea), were inactive against AH-13 and slightly active against L-1210. On the contrary, 1, 1'-polymethylene-bis(3-substituted 1-nitrourea) derivatives were more active against AH-13 than against L-1210. The nitrosoureas which had bis(2-chloroethyl) group at the terminal were highly active against AH-13 and L-1210. One of denitrosated derivatives, 1, 1'-ethylene-bis[3-(2-chloroethyl)urea], was active against AH-13 alone. In addition, diisocyanates, nitrourea, ammonium carbamate, and 1-methyl-1-nitrourea, which are related to the nitrosourea compounds, were also tested for their activity against AH-13 and L-1210. Diisocyanates and nitrourea were active against AH-13 alone, while other compounds were all inactive.

Severe generalized glutathione reductase deficiency after antitumor chemotherapy with BCNU" [1,3-bis(chloroethyl)-1-nitrosourea

Patients receiving BCNU [1,3-bis(2 chloroethyl)-1-nitrosourea] acquire a profound deficiency of erythrocytic oxidized glutathione reductase (GSSG-R) within minutes after the first intravenous injection of a single therapeutic dose (75 mg/M.2) of the drug. This effect is not accompanied by changes in the activites of 19 additional erythrocytic enzymes tested, is reproducible in vitro in a dose-related manner, and is not caused by the antitumor agents administered concurrently with the nitrosourea. The inactivation of erythrocytic GSSG-R results in decreased levels of reduced glutathione (GSH), marked GSH instability and disturbed hydrogen peroxide removal with a positibe ascorbate cyanide test and leads to increased susceptibility to oxidative hemolysis, particularly in glucose-6-phosphate dehydrogenase (G-6-D)-deficient patients. BCNU inhibits GSSG-R irreversibly, probably through alkylation rather than carbamylation, and the reappearance of enzyme activity in vivo after each chemotherapy pulse depends on the capacity of the marrow to release erythrocytes with normal activity formed during the drug-free interval. BCNU inhibits GSSG-R not only in erythrocytes but also in human leukocytes and platelets, as well as in yeast, monkey erythrocytes, and all the organs tested in the mouse. This generalized, severe, and specific GSSG-R deficiency caused by therapeutic doses of BCNU may enhance or mediate the toxic and antitumor effects of the nitrosourea and provides a simple yet sensitive biochemical means of monitoring bone marrow reserve in patients receiving multiple courses of chemotherapy with this agent.

Effect of 1-(2-chloroethyl)-3-(beta-D-glucopyranosyl)-1-nitrosourea on experimental tumors.

A newly synthesized water-soluble nitrosourea derivative, 1-(2-chloroethyl)-3-(beta-D-glucopyranosyl)-1-nitrosourea (GANU; NSC-254157) has marked activities against experimental tumors such as lymphoid leukemia L-1210, ascites sarcoma- 180, ascites hepatoma AH-130, and Walker carcinosarcoma-256. A single intraperitoneal injection of the compound is more effective than successive injections on the L-1210 system. An especially interesting point is that both the single intraperitoneal and single oral administrations 2 days after tumor implantation showed a high effectiveness. In addition, growth of the mammary adenocarcinoma transplanted subcutaneously on the back of mice was also considerably suppressed by successive intraperitoneal injections of the compound.

Comparative studies on the antitumor activity and the bone marrow toxicity of 1-(beta-D-glucopyranosyl)-3-(2-chloroethyl)-3-nitrosourea and 2-(3-(2-chloroethyl)-3-nitrosoureido)-D-glucopyranose.

Antitumor activity and bone marrow toxicity of a new nitrosourea analog, 1-(beta-D-glucopyranosyl)-3-(2-chloroethyl)-3-nitrosourea (GANU), were compared with those of 2-(3-(2-chloroethyl)-3-nitrosoureido)-D-glucopyranose (Chlorozotocin) and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). GANU was found to be highly active against mouse leukemia L-1210 when administered intraperitoneally or intravenously, being the same degree as Chlorozotocin. Even by oral route, GANU exhibited significant activities, whereas Chlorozotocin failed to show any activities by this route. Studies on the bone marrow toxicity as measured by the depression of white blood cell counts and the marrow cellularity revealed that both GANU and Chlorozotocin were less toxic than BCNU. GANU, however, weemed to be rather more toxic than Chlorotocin.

Comparison of the effects of cysteine upon the decomposition of nitrosoureas and of 1-methyl-3-nitro-1-nitrosoguanidine

Comparison of the effects of cysteine upon the decomposition of nitrosoureas and of 1-methyl-3-nitro-1-nitrosoguanidine