Molecular carriers with alkylating sites and sites endowed with antimetabolic activity were synthesized.

Phenylalanine and hydroxyphenylalanine having a dichlorodiethylamino group in the benzene ring were chosen as alkylating agents because of their capability to form peptides with natural and antagonist aminoacids.

The chemotherapeutic screening was carried out according to CCNSG rules with the only variant that the determination of the weight of the tumors of the treated mice was carried out on the day subsequent to that indicated by the CCNSC, i.e. at the 9th day after tumor implantation. In this same day the spleen weight was determined also. On the previous day, the white cell count was carried out and in way it was allowed an evaluation of the hemotoxicity.

The optical isomerism of the compounds plays a fundamental rôle in the chemotherapeutic activity.

Examples of different isomers of the tripeptide phenylalanyl-ethionyl-m-sarco-lysine and of the tetrapeptide arginyl-p-fluorophenyl-alanyl-glycyl-m-sarcolysine, endowed with markedly different chemotherapeutic activities (from o to 90) in relation to the different stereochemical configuration are reported.

Oxidative phosphorylation, ATPase, glycolysis, Nadase, succinic dehydrogenase, cytochrome-oxidase, glutamic dehydrogenase, lactic dehydrogenase amino acid oxidase, proteolysis were studied in biochemical pharmacology investigations.

The active compounds bring the phosphorylation ratio to zero in Sarcoma 180 mitochondria at doses reducing the P/O by 40-50% in normal liver mitochondria.

Interesting observations are pointed out for other enzyme systems, showing the specificity of the activity of some peptides at the biochemical level on tumor enzyme systems in comparison with the same enzyme systems of normal tissues.

An evaluation of the antimitotic activity of a group of antitumoral agents was performed. Their action was first assayed on chick embryo blood forming tissue, determining its survival, mitotic index and mitotic differential count: the statistically most active compounds were demecolcin, vinblastine and cyclophosphamide.

The same compounds were also tested on the in vitro blastic transformation of human leukocytes and their incorporation of tritiated DNA and RNA precursors.

The most active compounds in this assay was 5 fluorouracil; a lesser degree of inhibition was caused by vinblastine, cyclophosphamide and mechloretamine.

The effect of a single massive dose of the same compounds in vivo was also studied determining the in vitro activity of leukocytes of such patients, removed 48 hrs after the administration.

Preliminary results show that such leukocytes lose in variable degree their phyto-responsiveness in vitro.

Antimitotic agents induce pathological alterations by suspension of the normal cellular renewal: it results the picture of the so called « aregenerative pathology ». Moreover, they induce cytological abnormalities, like cellular vacuolization, alterations of the enzymatic cellular pattern, cellular giantism, etc. These alterations constitute the « cytological dysplasia by antimitotic drugs ». They are easily recognizable in many organs, i.e. in the haemopoietic system, lungs and pancreas. Particularly evident is the cellular giantism in the labial epithelia: in some of these cells of gynecologically normal women two Barr bodies are observed.

Daunomycin (Da) a metabolite of Streptomyces peucetius has a cytotoxic and antimitotic activity on normal and neoplastic mammalian cells grown in vitro and strongly inhibits a variety of experimental tumors.

The cell damage induced by Da is mainly nuclear.

A finely granular appearance of the chromatin and marked alterations in shape and size of nucleoli in resting cells and many mitotic aberrations in mitotic cells were observed.

Biochemical and autoradiographic researches show that the binding of Da with DNA causes a reduction of the DNA and RNA synthesis, especially of the RNA which is synthesized in the nucleoli and then passes into the cytoplasmic ribosomic RNA.

Treatment with Da on synchronized cells shows a marked drop of the mitotic index and appearance of mitotic anomalies when the cells are treated in S and G2 phases.

This reduction keeps also in the second mitotic wave. A reduction of the mitotic activity is observed also if the cells are treated near the middle of the interphase.

Da causes a reduction in the percentage of the nuclei labelled with 3H thymidine and in the number of grains per nucleus, when the cells are treated in S phase, in the very beginning and middle of interphase.

A report is given on various forms of administration of Trenimon for local treatment of neoplasms of the serous membranes. For supervision and adjustment of the chemotherapeutic effect supravital staining with acridin orange and phase-contrast microscopy of the untreated effusion sediment are especially suitable. This facilitates distinction between newly formed and preformed granules, which is of importance for the diagnosis. Inhibition of dye-induced production of granules is a very sensitive criterium for assessment of cell vitality. The development of regressive changes in the tumour cells caused by chemotherapy is discussed with reference to micrographs of a metastatic pleural sarcomatosis. Electron-microscope studies on the exudate suggest that prior to necrobiosis an increased transfer of the granular nucleolar component into the cytoplasm takes place. This may be caused by a true increase in the transfer of nucleolar RNA towards the cytoplasm or by an inhibition in the late S-phase.