Spin labeled amino acid nitrosourea derivatives--synthesis and antitumour activity.

The synthesis of three spin labeled derivatives of N-[N'-(chloroethyl)-N'-nitrosocarbamoyl] amino acids is reported. The new nitrosoureas are obtained by condensation of the corresponding N-[N'-(2-chloroethyl)-N'-nitrosocarbamoyl] amino acid with 2,2,6,6-tetramethyl-1-oxyl-4-aminopiperidine using dicyclohexylcarbodiimide. Their chemical structures are confirmed by elemental analysis, IR, MS, and EPR spectroscopy. All newly synthesized compounds showed high antitumour activity against the lymphoid leukemia L1210 in BDF1 mice.

Nanoparticles as drug carriers for vinblastine. Acute toxicity of vinblastine in a free form and associated to polybutylcyanoacrylate nanoparticles.

The possibility of reducing toxicity of Vinblastine by fixing it in polybutyl-2-cyanoacrylate nanoparticles was studied. A significant reduction of mortality of mice was recorded after a single intraperitoneal (i. p.) injection of nanoparticle-associated Vinblastine. A wide range of doses of Vinblastine (1.04-6.25 mg/kg) were used. There was a considerable decrease of leucopenia caused by Vinblastine-loaded polybutyl-2-cyanoacrylate nanoparticles as compared to that induced by free Vinblastine.

Cytotoxicity on L1210 leukemic cells of beta-amanitin-concanavalin A and phallacidin-concanavalin A conjugates.

The conjugates beta-amanitin-concanavalin A and phallacidin concanavalin A were tested for direct cytotoxicity on L1210 lymphocytic leukemia cells by a combined in vitro-in vivo bioassay. Both conjugates exerted strong direct cytotoxicity on the tumour cells.

Synthesis and antitumour effect of N alpha-acyl derivatives of L-cystine-bis [N,N-di(2-chloroethyl)]dihydrazide.

A series of Na-acyl derivatives of L-cystine-bis [N,N-di(2-chloroethyl)]dihydrazide was synthesized. The effect of the acyl substituent on the antitumour activity of the synthesized compounds was studied. It was demonstrated that the introduction of short-chain Na-acyl substituents resulted in substances with higher antitumour effect and lower toxicity.

Synthesis and antitumour activity of 4-nitroso-4-(2-chloroethyl)semicarbazides.

1-Methyl-1-(2-chloroethyl)-4-nitroso-4-(2-chloroethyl)semicarbazide, 1,1-di-(2-chloroethyl)-4-nitroso-4-(2-chloroethyl)semicarbazide and 1,1-di-(2-bromoethyl)-4-nitroso-4-(2-chloroethyl)semicarbazide, which are a novel class of nitrosoureas containing hydrazinomustard residue, have been synthesized. A dose-dependent antitumour activity was found with the three tested compounds.

Chemo- and immunotherapy of an adenovirus-induced transplantable sarcoma in hamsters.

The subcutaneous transplantable adenovirus sarcoma (TAVS) in hamsters was created in 1972 at the Oncological Research Institute and maintained by serial subcutaneous transplantation. It showed the highest sensitivity against some alkylating drugs and antimetabolites--cyclophosphamide, sarcolysine, methotrexate and 6-mercaptopurine. In some degree, TAVS is able to differentiate antitumor drugs of one group by the intensity of their antitumor activity. Among the drugs, cyclophosphamide was the most active and 6-mercaptopurine and 5-fluorouracil the least active. Antitumor drugs of plant origin, antibiotics and methyl-CCNU had a weak activity on subcutaneous TAVS. Intramuscular TAVS showed a similar sensitivity, with some differences for olivomycin, bruneomycin and vinblastine. Intracerebral TAVS was sensitive against antitumor agents penetrating through the hemato-encephalic barrier and which were active against its subcutaneous and intramuscular form. BCG vaccine and levamisole applied separately did not show any activity on the growth of TAVS. Combined immunochemotherapy with cyclophosphamide plus BCG gave a better enhancement of the antitumor effect of the cytostatic than that of the combination of methotrexate plus BCG and cyclophosphamide plus levamisole. These results showed that TAVS in hamsters may be used as a suitable experimental model for pharmacological studies of antitumor agents and combined immunochemotherapy.

Synthesis and study of spin-labeled nitrosoureas.

For the first time we have synthesized spin-labeled nitrosoureas and have studied their properties--reduction of the iminoxyl group by vitamin C leading to the formation of the corresponding hydroxylamine derivatives and degradation in the presence of an aminoradical, leading to biradicals. The ESR spectra of biradicals in methanol have nine hyperfine resonance lines. The spin-labeled nitrosoureas have shown a high antitumor activity against the L 1210 lymphoid leukemia and P 388 lymphocytic leukemia in BDF1 mice. A study of a broad range of transplantable tumors is in progress.

Influence of antitumor drugs of natural origin on the intramuscular and subcutaneous form of five transplantable tumor models.

The influence of six antitumor drugs of natural origin (rubomycin, bruneomycin, olivomycin, mitomycin C, vinblastine, and vincristine) on five transplantable tumor models (sarcoma 37, sarcoma 180, Ehrlich tumor, RL-67 and TAVS) was investigated. Each tumor was transplanted subcutaneously and intramuscularly, bilaterally, on one animal. Marked differences in the sensitivity between subcutaneous and intramuscular form of Ehrlich tumor and more slightly of TAVS were established. The used experimental regimen held out possibilities for saving labor, animals and substances as well as for the study of potential antitumor substances of natural origin at maximum equalized biological conditions.