Zeitschrift fur Krebsforschung und klinische Onkologie. Cancer research and clinical oncology最新文献

Di-n-propylnitrosamine (DPN) and methyl-n-propylnitrosamine (MPN) induced mainly respiratory tract neoplasms in female NMRI mice after subcutaneous administration. The majority of tumors occurred in the nasal cavities, although significant incidences were also found in the larynx, trachea and stem bronchi. Treatment with both substances additionally resulted in vascular neoplasms of the liver, while DPN only caused tumors in the pharynx, esophagus and forestomach.

The cytostatic efficacy of the antibiotics adriamycin, daunomycin and actinomycin D and of DNA-complexes of these compounds was compared in an Ehrlich ascites tumor in vivo. Various doses of the individual drugs and their DNA-complexes were injected intraperitoneally into female NMRI mice following 8 days after inoculation of 10(6) Ehrlich ascites cells. Survival analyses of animals demonstrated that by addition of DNA therapeutic indices were improved for adriamycin, daunomycin and actinomycin D, DNA alone had no effect on this tumor. Since earlier biochemical data (Seeber et al., 1977) had shown decreased in vitro cytotoxicity of DNA-bound antibiotics, this increase in therapeutic efficacy is probably due to an altered pharmacological behaviour after complex formation with a prolongation of effective intraperitoneal drug levels and decreased systemic toxicity.

Annulate lamellae were observed in untreated in vivo ascites tumor cells with a diminished cytoplasmic microtubule complex. The ascites tumor cells in vitro responded to prolonged colchicine treatment with the formation of annulate lamellae. Simultaneous treatment with dibutyryl cycle adenosine monophosphate and colchicine seemed to enhance the formation of annulate lamellae. Single pore complexes were found in the granular endoplasmic reticulum in untreated tumor cell in vitro, and a close association of microtubules with the nuclear envelope was observed. Our results suggest the existence of an interrelationship between the cytoplasmic microtubule complex and certain other cell structures, i.e. the nuclear envelope, annulate lamellae, and single pore complexes.

Diethylnitrosamine (DEN) was applied orally to a total of 250 female Wistar rats in a single dose (d) of 3 mg/kg body weight 5 times a week for a duration of 20 weeks. After approximately 150 days exploratory laparotomy was performed to all animals. By inspection of the liver they were divided into 4 stages of disease according to the extent of cancer formation. The reaction of rats with DEN induced liver tumors was tested using a 4-drug combination chemotherapy with different equitoxic doses of Adriamycin (Adm), Methotrexate (Mtx), 5-Fluorouracil (5-FU) and Cyclophosphamide (CP). No benefit of drug treatment could be noted. In drug treated animals no decrease in the development of the liver tumors, in the frequency of metastases nor in the frequency of tumors of other origin could be demonstrated. The parallels of chemotherapy in chemically induced liver cancer to clinical experience are discussed.

There was more persistent methylation of liver DNA from rats given [14C]DMN if it was given during liver regeneration, either after partial hepatectomy or a dose of CCl4 compared to otherwise untreated rats. During liver regeneration, DMN metabolism was slowed making the active metabolites available for longer.

Drugs entrapped in liposomes (artificial lipid vesicles) exhibit different pharmacokinetics after intravenous application than drugs injected in a free form. The folidacidantagonist methotrexate can be entrapped in liposomes in a therapeutically useful concentration (0.5 mg MTX/ml) and can be stored with high stability of entrappment. After intravenous injection into the tail vein of mice liposomes entrapped methotrexate is found more enriched in cell systems with high rate of endocytosis and not eliminated by the kidneys within 3 h like free methotrexate. It can be shown, that for the organs liver, spleen, kidney, gut, lung, and blood over a 6 h period liposomes entrapped methotrexate is enriched in the tissues and that for example after 6 h the methotrexate level in the liver is 20 fold higher in comparison to free injected methotrexate.

Histochemical activity of acid DNAse, intensity of nucleic acid staining and histological alterations in mouse interfollicular epidermis (I.F.E.) were investigated after a single dose or after chronic topical administration of two hyperplastic agents, of which one (croton oil) was a potent tumor promotor, and the other one (podophyllin) did not promote skin carcinogenesis. Podophyllin induced intense uniform I.F.E. hyperplasia without any proliferation of poorly differentiated basal cells, without increased nucleic acid staining and without any appreciably decreased acid DNAse activity. On the other hand, croton oil (as well as TPA) produced almost immediate, distinct hyperplasia of poorly differentiated basal cells with increased intensity in the staining of both nucleic acids and nearly complete deficiency in acid DNAse activity. Similar histochemical and histological patterns were observed at the sites of wounding hyperplasia in untreated control mice. Such wounding hyperplasia was thought also to be a tumor promoting factor. It was suggested that the decrease in acid DNAse activity which occurred almost immediately after administration of potent tumor promoters and which could not be induced by a hyperplastic agent without tumor promoting action may have a particular importance in the mechanisms of tumor promotion.

Sixty-one patients with locally advanced squamous cell carcinomas of oral cavity and oropharynx were treated with chemotherapy, intravenously applied, in addition to radiation and/or surgery. An attempt was made to synchronize the tumor cell population by application of low doses of Vinblastine and the subsequent chemotherapy was based on the uptake of 99m-Tc --labelled Bleomycin in the tumor as an indication of synchronization. Increased number of mitoses in aspiration biopsy specimens and shift in the DNA distribution pattern on DNA histograms were taken as indicative of synchronization. A 50--100% regression of the tumor was achieved in 19 out of 38 patients with residual or recurrent tumors. The results were better in those patients, who received chemotherapy based on individual Tc-Bleomycin uptake curves. In 23 patients with previously untreated T3 tumors of oral cavity and oropharynx the results were somewhat better, but there was not statistically significant improvement on attempts with synchronization in this small series. There were no serious complications connected with chemotherapy.

The present investigations showed that assumed and established metabolites of dipropylnitrosamine and dibutylnitrosamine reach the Syrian hamster fetus after subcutaneous (s.c.) treatment of their mothers (at day 14 of gestation). The compounds [2-hydroxypropylpropylnitrosamine, HPPN; 2-oxopropylpropylnitrosamine, OPPN; methylpropylnitrosamine, MPN; N-nitrosobis(2-hydroxypropyl)amine, BHP; and 4-hydroxybutylbutylnitrosamine, HBBN] were still present in the examined tissue (maternal blood, placenta, fetus, amniotic fluid) 4--6 h after s.c. injection. The overall incidence of transplacentally induced tumors was lower in the F1- than in the P-generation and comparatively longer latencies were also observed in the F1- generation. However, in some groups low incidences were found of tumors which did not occur in the mothers (i.e., nasal cavities: BHP, HBBN; trachea: HBBN; lungs: HPPN, BHP, HBBN; liver: OPN, MPN, BHP, HBBN). Compared to exposure at early gestation, the transplacental carcinogenic effect increased at day 14 of gestation. Neoplasms originating in other organs were not associated with a transplacental effect of the examined nitrosamines.