Bovine leukosis virus: recloning of specific DNA fragments.

DNA fragments generated by Bam HI restriction endonuclease digestion of the provirus of bovine leukosis virus (BLV) was recloned in several plasmids. Recombinant plasmids containing X-region, env gene and a part of pol gene were prepared in pBR322, and in a plasmid containing promotor PR. Fragments env gene and a part of pol gene inserted were also into the pSV2-dhfr plasmid which has the both bacterial and eukaryotic promotors together with the gene for folic acid reductase. The expression possibility of these inserted BLV sequences either in mammalian cells after transfection or in bacteria is now tested.

Bovine leukemia provirus in the DNA of different infected host cells.

Bovine leukemia provirus is reported to be integrated in the DNA of different infected mammalian cells. We observed morphological transformation in BLV infected sheep fetal spleen, kidney, thymus and sternal cultures. The presence of BLV specific sequences in their genome was established after digestion with the restriction endonuclease EcoRI and hybridization with a BLV specific probe. Human myeloma ARH77 and myeloid K562 cells infected with BLV were virus productive as detected by a reverse transcriptase assay. The presence of proviral sequences was confirmed after Southern blotting analysis. Restriction digestion by SacI enzyme yielded a complete 8.9 kb BLV provirus in infected ARH77 cells and a smaller 7.5 kb BLV fragment in infected K562 cells.

Hodgkin's disease as a failure of immune regulation: a re-interpretation of the epidemiological findings.

A failure of immune regulation has been often suspected as the basic condition leading to the development of Hodgkin's disease (HD), but the precise nature of this immune defects has not been defined. It is shown here that most of the epidemiological features fit the hypothesis of an increased risk for HD linked to an immune disbalance between a weak immune suppressor activity (ISA), and an enhanced polyclonal B cell activation (PBA). Few infections in childhood and an "untrained" immune system would lead to a weak ISA as the main risk factor among adolescent and young adults in the developed world, while an enhanced PBA due to chronic parasitic infections and malnutrition could explain a relatively high risk for HD among small children in undeveloped countries. The different histologic types of HD may reflect a variable contribution of a weak ISA, or an enhanced PBA under different conditions.

Genetic background of high incidence of spontaneous tumors in BDX rats.

Genetic background of high incidence of spontaneous tumors in BDX rats was investigated with respect to susceptibility to physical or chemical agents and immune response. Percentages of colony forming ability of normal embryo fibroblasts from BDX rats after exposure to various doses of ultraviolet (UV) light, X-rays and Mitomycin C were almost identical to those of cells from control F344 rats. Furthermore, BDX rats showed similar level of rosette forming cells, blastogenic response, and plaque forming cell (PFC) response as compared with WKA rats used as a control, although BDX rats showed higher natural killer (NK) cell activity. These results indicate that high incidence of spontaneous tumors in BDX rats is not due to some defects in DNA repair or immune response. In 3 methylcholanthrene (MCA) carcinogenesis, however, BDX rats developed tumors very early; the mean latency periods for development of MCA-induced tumors were 135 days in BDX rats and 256 days in F344 rats. Measurement of the inducibility of specific aryl hydrocarbon hydroxylase (AHH) activity in liver microsomes revealed that BDX rats showed higher inducibility than F344 rats: the inducibilities were 23.7 in BDX rats and 5.7 in F344 rats. Higher inducibility of AHH in BDX rats seemed to be parallel to earlier development of tumors in MCA-carcinogenesis in the rats. Thus, it is most likely that high incidence of spontaneous tumors in BDX rats is due to high susceptibility to some chemical carcinogens which may be contained in foods or drinking water in a small dose.

Haptoglobin type in connection with mean age at first breast cancer signs?

In breast cancer patients divided into groups according to haptoglobin (Hp) type (519 patients), blood group (ABO) (433 patients) or Rh factor (358 patients) the mean age at first disease manifestation was calculated. The results indicate that in Hp 1 bearers breast cancer appears at significantly lower age (49 years) as compared to Hp type 2-1 (53.3 years) or Hp 2 (53 years). In blood groups the mean age at first cancer signs raises from 48 years in the AB group to 53.1 years in the A group, only the difference between A and AB being significant. However, these preliminary results require confirmation in larger patient series.

Effect of 13-cis-retinoic acid on the spontaneous thymic lymphoma development in AKR mice.

The aim of the study was to analyze the incidence of spontaneous thymic lymphomas in AKR mice kept on a diet with normal and excess retinoid content. The mice whose diet was supplemented with 13-cis-retinoic acid (250 mg per kg chow) developed less lymphomas than those kept on a standard diet (15 mg per kg chow). The effect of cyclophosphamide on the early stage of lymphomogenesis was tested using a single dose (100 mg per kg body weight), injected intraperitoneally to AKR mice. Increased incidence of lymphoma following cyclophosphamide administration was observed as result of a) low sensitivity of prelymphoma and lymphoma cells and/or b) immunosuppressive effect of cyclophosphamide.

Effect of mitoxantrone on human chronic myeloid leukemia cells in vitro, combined with hyperthermia.

Mitoxantrone, a new anticancer drug has DNA-binding properties similar to anthracycline antibiotics. In the present studies, effect of the drug has been tested in vitro on human chronic myeloid leukemia cells at 37 degrees C and 42 degrees C. Inhibition of 3H-tritiated thymidine incorporation in the drug-treated cells compared with untreated cells has been used as the parameter of cytotoxicity of the drug and hyperthermia. Cell samples from 11 CML patients who did not receive any chemotherapy showed less response to the drug at 0.5 micrograms/ml and 1 microgram/ml at 37 degrees C. Exposure of CML cells to 42 degrees C for 2 h indicated 13 to 44% inhibition in 3H-TdR incorporation. However, when CML cells were exposed to mitoxantrone for 2 h at 42 degrees C the 3H-thymidine incorporation was inhibited to the extent of 27 to 71%, indicating greater cellular damage with this combination.

Two-dimensional analysis of metabolically and cell surface radiolabeled proteins of some human lymphoid and myeloid leukemia cell lines. I. 35S-methionine labeled, lactoperoxidase radioiodinated and 3H-reductively methylated proteins.

Cell surface and cytoplasmic polypeptides of some human hemopoietic cell lines were radiolabeled by three different techniques: 35S-methionine metabolic radiolabeling, lactoperoxidase catalyzed radioiodination and reductive methylation with formaldehyde and tritiated sodium borohydride. Two-dimensional patterns of 35S-methionine labeled proteins revealed more than 500 separated protein spots with essentially similar general aspects of all examined cell lines, sharing major polypeptides such as those with electrophoretic mobilities of major cytoskeletal proteins. 125I-lactoperoxidase radio-iodinated cell surface protein patterns contained about 30 separated protein macromolecules with some marked differences between lymphoid versus myeloid lines and also between individual cell lines. Two-dimensional patterns of tritiated membrane polypeptides consisted of approximately 200 separated protein spots, some prominent of them appeared with electrophoretic mobilities of major cytoskeletal proteins being common to both 35S-methionine and reductive methylation patterns. Two-dimensional patterns of 35S-methionine labeled and cell surface radioiodinated proteins immunoprecipitated by monoclonal antibodies Bra30 and HL39, recognizing MHC class II antigens, appeared as bimolecular complex of larger acidic and smaller basic chains structurally corresponding to the expected two-dimensional patterns of MHC class II antigens.

Two-dimensional analysis of metabolically and cell surface radiolabeled proteins of some human lymphoid and myeloid leukemia cell lines. II. Glycosylated and phosphorylated proteins.

Cell surface glycoproteins, radiolabeled by sodium metaperiodate/tritiated borohydride technique and cell phosphoproteins, metabolically radiolabeled by 32P-orthophosphate were analyzed by two-dimensional electrophoretic analysis in some myeloid and lymphoid leukemia cell lines. Some markedly expressed major glycoproteins were predominant in some of cell lines (such as 95k and 100k glycoproteins with marked charge heterogeneity in non-T, non-B acute lymphoblastic leukemia cell lines NALM 6 and NALM 16), but markedly quantitatively reduced in other examined cell line, such as lymphoblastoid cell line UHKT 34/2. 32P-orthophosphate radiolabeled phosphoprotein two-dimensional patterns of examined lymphoid leukemia cell lines were essentially similar, with some minor differences, in examined lymphoid and myeloid leukemia cell lines, such as marked expression of a series of large phosphoproteins in the molecular weight range 80-100k in lymphoid cell lines and almost complete absence of these phosphoproteins on examined myeloid leukemia cell lines. Another configuration of acidic phosphoproteins (30-35k) exhibited individual cell line variability and differences between both individual myeloid leukemia cell lines and between lymphoid and myeloid cel lines examined.

An attempt at applying epiadriamycin to the patients for whom doxorubicin is cardiologically contraindicated.

Administrating Epi-ADR (Epiadriamycin) to the patients for whom ADR was cardiologically contraindicated did not cause significant complications. No complications occurred in the patients treated with Epiadriamycin, after they had completed a full course of maximal dose of ADR. The trial was conducted in close cooperation with a cardiological intensive care unit which is an essential arrangement in such clinical situation, until the optimal therapeutical method of administrating Epi-ADR is defined with special attention devoted to its critical dose.

Study of relationship between allogeneic transplantability of tumors and their effects on drug-metabolizing system in rats.

Effects of three different fibrosarcomas on the hepatic mixed-function oxidase system were studied in males of the Lewis inbred strain of rats. No association between graded potentiality of these tumors to grow across histocompatibility barriers and their suppressive effects upon the microsomal drug-metabolizing system was found.

Epidermal growth factor inhibits thymidine incorporation in Ehrlich ascites tumor cells in vivo.

The effects of in vivo injection of epidermal growth factor (EGF) on mice bearing Ehrlich ascites tumors have been studied. Epidermal growth factor was rapidly distributed, reached tumor cells and recognized specific cell membrane receptors. The effects of the subcutaneous injection of EGF were manifested by a decrease of measurable membrane receptors and inhibition of thymidine incorporation to TCA-insoluble material. The effect on thymidine incorporation was dose-dependent and independent on the source (murine or human) of EGF. These results suggest that high doses of EGF could eventually be used for inhibition of the cell proliferation in some tumors.

Structural changes induced by heparin in Zajdela ascites hepatoma cells.

By method of light and electron microscopy the influence of heparin (0.1%) sodium heparinate) on Zajdela ascites hepatoma cells was studied. To provide penetration of heparin into cells, the latter were treated with low-concentration detergent--Triton X-100. Heparin causes increase of cells observable by phase-contrast method, and homogenization of the karyoplasm. When examining stained preparations light-optically, chromatin is distributed evenly and structurelessly over the whole cell. Streaks of DNA-containing material protrude into the cytoplasm. Electronograms show lowering of electron density of cells, transformation of chromatin fibrils into a thin-fibrillar network, vanishing of nucleoli, and appearance of structureless globules about the size of 100 nm. The observed changes are discussed in the light of data on the anti-cancer action of heparin.

Ferritin-bearing lymphocytes in Hodgkin's disease.

In view of the reported association of Hodgkin's disease (HD) and ferritin, ferritin-bearing lymphocytes were followed during 2-year period in 79 HD patients. Indirect immunofluorescent method was used to evaluate the percentage of ferritin positive cells. In 22 untreated patients a high percentage of ferritin-bearing circulating lymphocytes (mean value 37.3%) was found. In regard to the extent of the disease higher values were found in clinical stage III and IV (mean value 40.6%) as compared to the stage I and II (mean value 26.2%). Similarly, 17 patients in relapse and with disease progression had mean values 41%. These proportions of cells were significantly lower in 44 patients in complete remission with mean value of 8.7% (60 examinations). In 30 healthy controls the mean value was 1.4%. Repeatedly performed examinations of ferritin-bearing lymphocytes during the follow-up period in 17 patients showed to be an important prognostic tool. A negative correlation of ferritin-bearing lymphocytes with E-rosette-forming cells was found. Iron content in peripheral blood lymphocytes was confirmed cytochemically after pre-incubation with antiferritin antibody. The results support the presumed role of ferritin in impaired cellular immunity in HD and suggest diagnostic and prognostic value of the examination of ferritin-bearing lymphocytes in HD.

Colicinogeny in colorectal cancer.

Colicins, bacteriocins of Escherichia coli and related bacteria of Enterobacteriaceae family, form a very heterogeneous group of antibiotically active substances of proteinaceous material. Antitumorous effect of colicins have also been demonstrated experimentally. The large bowel has been found to be a site of their native action. Therefore, our work has been aimed at investigating colicinogenicity in patients with colorectal carcinoma. From a total number of 77 patients with colorectal carcinoma, colicinogenic Escherichia coli was found in 32 persons (41.6%), whereas from a total of 160 control clinically healthy persons, colicinogenic Escherichia coli was found in 102 persons (63.8%). The difference is statistically significant (p less than 0.05). The absence of colicinogenic Escherichia coli may be one of the factors contributing to the origin and development of colorectal carcinoma in some of the patients studied. Studies of patients with adenomatous polyps, members of colon cancer families, and large prospective studies of the general population will be necessary to prove this hypothesis.

Results and further perspectives of plasmocytoma chemotherapy.

Polychemotherapy has improved prognostic parameters of survival in patients with plasmocytoma. The mean survival in patients given long-time prednisone and melphalan treatment is 20 months, in those given polychemotherapy over 30 months. In patients with a slow disease progression the combinations COPP and VMCP give satisfactory results in about 40%, but in a majority of patients more effective treatment is necessary. The authors compare the 5-year survival of two polychemotherapy groups with the prednisone and melphalan group. The mean survival after prednisone and melphalan was 33 months, after polychemotherapy (groups COPP, VMCP) 46 months and 57 months (VMCP + M2), respectively. Survival time was influenced by the clinical stage.

Monitoring of effects of cis-diamminedichloroplatinum (II). Part III. Effect of platinum complexes on PHA-stimulated proliferation of human peripheral blood mononuclear cells in vitro.

The effect of the platinum complexes cis-DDP and CBDCA on the functions of human peripheral blood mononuclear cells (PBMC)--viability, proliferating activity after polyclonal stimulation with phytohemagglutinin is followed in an in vitro study. Both the platinum complexes (at concentrations 10(-5) up to 10(-9) mol/l) inhibit significantly the proliferating activity of PBMC without affecting its viability, i.e. integrity and permeability of the cell membrane structures. As to effectivity, cis-DDP has shown itself a more effective inhibitor of cellular proliferation than CBDCA of which 10-100 times higher concentrations are required to achieve the same inhibitory effect in dependence on the temporal relation to the application of phytohemagglutinin. The highest inhibitory effect is noted when cis-DDP is applied either simultaneously with, or 48 h after PHA, i.e. at the stage of maximum proliferating activity. The results bring support to the assumed mechanism of action of the above platinum complexes--intervention into DNA synthesis. Since the test of blastic transformation of PBMC is held to be an image primarily of the function of T lymphocytes, it may be inferred that platinum cytostatics can affect cell-mediated immunity also in patients.

Morphological and immunohistochemical study in Hodgkin's disease.

Histogenesis of different microscopical types of Hodgkin's disease was investigated in a series of 19 patients by morphological and immunohistochemical methods. The main changes affecting the lymphatic system occur in perivascular areas, which contain a great amount of thymic factor. The Hodgkin's and Reed-Sternberg cells appear to arise from the perivascular mesenchyme and some of them have cross-striated cytoplasm.

The effect of fibrinogen-methotrexate derivatives on HeLa cell growth.

Proteolytic cleavage of bovine fibrinogen with covalently bound methotrexate (MTX) was studied using four different proteolytic enzymes--trypsin, chymotrypsin, pepsin, and cathepsin D and the interaction of the modified fibrinogen (or fibrin) with HeLa cells was investigated. The presence of fibrin-MTX derivative did not induce any significant morphological alternations of cells. The fibrin-MTX derivative in the gel form was solubilized easily by the action of all proteinases investigated, hydrolysis of highly crosslinked denatured fibrin-MTX in suspension proceeded slower. The solubilized fibrin-MTX degradation products had a strong inhibiting effect on the growth of HeLa cells cultured in monolayer indicating the liberation of chemotherapeutically active MTX from its fibrin derivative.

Change of mutagenic activity of N-methyl-N-nitrosoguanidine during its decomposition studied by SOS chromotest.

N-methyl-N-nitrosoguanidine (MNNG) decomposition kinetics in H2O was studied under in vitro conditions by spectrometry in different buffers and at different pH. Parallely the change of mutagenic activity of decomposing mixture was studied by SOS chromotest (in which the change of beta-galactosidase was observed). The MNNG decomposition was confirmed to be the reaction of the pseudofirst order. MNNG mutagenic activity decreases parallely with MNNG decomposition. From the observed facts it has been concluded that the MNNG decomposition proceeding outside the biological target gradually leads to the inactive stable decomposition products.

Results of genotoxicity testing of theophylline on bacteria and two lines of mammalian cells.

In study of the genotoxic effects of theophylline, this substance was subjected to a series of tests. Its potential mutagenicity was followed at the level of both bacteria and mammalian cells. The capacity of the substance to damage human DNA was determined by the so-called DNA inhibition test and by the method of alkaline elution of DNA. In the absence of the enzymatic microsomal S9 fraction, theophylline showed very weak mutagenic effects on bacteria and mammalian cells. However, in both cases this weak mutagenic effect was eliminated through a simultaneous application of theophylline and the S9 fraction. The results of the remaining tests proved negative regardless of whether the S9 fraction was present or absent. Our results lead us to infer that theophylline exerts no genotoxic action under in vivo conditions.

The effect of a normal tissue radioprotector Adeturone on the radiation sensitivity of Lewis lung carcinoma: an enhanced response.

The effect of the normal tissue radioprotector Adeturone (S-2-aminoethylisothiuronium adenosine-5'-triphosphate) on the response of primary and metastatic Lewis lung carcinoma to radiation was evaluated. It was found that this compound enhanced the antitumor effect of whole-body and local radiation. In experiments with whole-body radiation Adeturone eliminated the lethality due to radiation toxicity (for a daily treatment schedule--10 X 1 Gy/fraction) or reduced it from 50% to 25% (for an intermittent schedule--3 X 3.34 Gy/fraction). Following local radiation treatment combined with Adeturone, a higher TWI%, longer tumor doubling time and longer mean survival time were recorded than for either treatment alone. An enhanced activity against metastatic growth of Lewis lung carcinoma to the lungs was also found with combined therapy.

The results of clinical trial within the framework of CMEA on surgical methods of mammary gland carcinoma treatment.

The results of joint clinical investigation performed by 8 oncological centers within the framework of CMEA countries are reported. Out of 816 patients with mammary gland carcinoma (MGC) of lateral localization, stage T1-2N0-1aM0, classical radical mastectomy by Halsted was carried out in 230 patients, mastectomy by Patey in 318 patients and conservative operation of radical resection type--in 218 patients. Specific characteristics of the disease progression were studied considering the time of development and incidence rates of local relapse or distant metastases depending on the type of surgery and MGC stage. High rates of 5-year survival were found for all types of surgery, mastectomy by Patey proving somewhat superior.

Pre-screening of carcinogens by studying of DNA synthesis inhibition and gene mutations in mammalian cells.

The ability to induce gene mutations at the HGPRT locus in Chinese hamster V79 cells and to inhibit DNA synthesis in human EUE cells has been followed in eighteen chemical substances and ultraviolet light. The aim was to determine whether following of inhibition of DNA synthesis in impaired human cells may serve as an indicator of the mutagenicity of the relevant chemical substance. The results permit us to assume that following of DNA synthesis, the so-called DNA-inhibition test provides a preliminary information on the genotoxicity of the chemical substance, although the degree of inhibition of DNA synthesis need not necessarily denote the measure of the mutagenic effect of the substance. As certain further tests, utilising in vitro mammalian cells, so also the DNA-inhibition test yields a certain percentage of false positive results. Hence, it is important to combine this test with further express in vitro tests on the level of mammalian cells.

Time trends in cancer incidence in the German Democratic Republic 1968-1981.

Cancer incidence data from the National Cancer Registry of the German Democratic Republic were analyzed over the period 1968-1981. A regression model of the form log y = a + bx was fitted to the annual age-standardized incidence rates. The average annual percentage change in rates was used to summarize the temporal trend in cancer incidence. The greatest increase in incidence occurred for cancers of the oral cavity and pharynx. The greatest decrease was seen for stomach (females), small intestine (males) and cervical cancers.

Tumor associated macrophage mediated lysis of autologous tumor cells.

Lysis of autologous tumor cells (ATC) mediated by the tumor associated macrophages (TAM) was studied by 4 h 51Cr-release assay at different days of growth of a transplantable ascites tumor, S-180, inoculated in adult male Swiss mice. The ATC were coated with serum of tumor bearing mice. On day 3 after tumor inoculation the TAM mediated a remarkable lysis of the tumor serum coated ATC. With advancement of tumor growth the cytolysis by TAM decreased gradually to the basal level at day 10 and totally abrogated at day 12. Also the binding of the tumor serum coated ATC by TAM varied at different days of tumor growth. At early phases of tumor growth high lytic activity of the TAM was correlated with augmented target binding. The observed lysis may be considered as antibody dependent cell mediated cytotoxicity (ADCC) extended by the TAM, since presence of specific tumor antibodies were demonstrated in the tumor serum used for coating ATC. No significant lysis was recorded when the ATC was coated with normal serum or used as such for direct lysis by the TAM. In vitro treatment of the TAM with suitable doses of Levamisole and Polyionosinic-polycyticyclic acid further augmented the TAM mediated high level of ADCC at day 3 with no change in its binding of ATC. The immunopotentiators enhanced both ADCC and target binding ability of the functionally depressed TAM at day 10.

A novel nontoxic alkyl-phospholipid with selective antitumor activity, plasmanyl-(N-acyl)-ethanolamine (PNAE), isolated from degenerating chick embryonal tissues and from an anticancer biopreparation cACPL.

A novel alkyl-phospholipid with selective antitumor activity was isolated from an anticancer biopreparation cACPL (crude anticancer phospholipids) and from tissues of degenerating chick embryos. The alkyl-phospholipid was isolated and purified by chromatographic methods using silicic acid column chromatography and thin layer chromatography. The chemical structure of the alkyl-phospholipid was characterized by thin-layer chromatographic analysis of the degradation products after enzymatic digestion with phospholipase C from Bacillus cereus and with phospholipase D, by two-dimensional thin-layer chromatography, infrared spectrum, and mass spectrometric analysis. The alkyl-phospholipid was identified as 1-O-alkyl-2-acyl-sn-glycero-3-phospho-(N-acyl)-ethanolamine, i.e. plasmanyl-(N-acyl)-ethanolamine (PNAE), the main molecular species being 1-O-octadecyl-2-oleoyl-sn-glycero-3-phospho-(N-palmitoyl)-ethanol-amine. PNAE exhibits a selective cytolytic effect on human tumor cells HEp-2, HeLa and T24 in tissue cultures at the concentration of 25 micrograms PNAE per ml and 66-98% inhibition of DNA synthesis in the human tumor cells at concentration as low as 2.5 micrograms/ml, but it does not inhibit at a 50-fold higher concentration the DNA synthesis and normal growth of human fibroblasts (cell line LEP). PNAE represents the main biologically active antitumor component of the cACPL biopreparation and exhibits a significant antitumor effect in vivo in B10/An mice bearing Mc11 fibrosarcoma. Possible molecular mechanism of the selective antitumor activity of PNAE is discussed, involving the selective disturbance of phospholipid metabolism in tumor cells, leading to progressive destruction of tumor cell membranes. The fact that PNAE is nontoxic and selectively active against tumor cells at nanomolar concentrations in vitro as well as in vivo, indicates the possibility of its clinical use. PNAE and cACPL biopreparation might provide a very useful new tool for human anticancer chemotherapy.

Modification of tumor cell sensitivity to antineoplastic agents lonidamine and bouvardin (NSC 259968) at elevated temperatures.

Lymphocytic leukemia P388 and Sarcoma-180 cells were exposed to various concentrations (0.01 mM to 0.04 mM) of lonidamine at 37 degrees C and 43 degrees C for 30 min and 60 min in vitro. Similarly combined effect of lonidamine and bouvardin on these tumor cells was also assessed at 37 degrees C and 43 degrees C. The effect was evaluated by comparing the rate of 3H-thymidine incorporation in treated cells to that of control cells. It was observed that at 37 degrees C lonidamine did not exert cytotoxic effect on P388 cells at prescribed time interval. Sarcoma-180 cells, however, showed significant sensitivity to the drug at 37 degrees C. Lonidamine exhibited greater cytotoxicity at 43 degrees C towards both P388 and Sarcoma-180 cells at 30 and 60 min exposure. Lonidamine also enhanced cytotoxicity of bouvardin in P388 and reversed the natural resistance of Sarcoma-180 cells to bouvardin at 37 degrees C.

Cancer chemotherapy induces a transient increase of serum-iron level.

Twenty eight consecutive patients with advanced solid malignancies were studied for variations in serum iron level after a first course of chemotherapy. Eleven different schedules involving twelve drugs were administered. Serum-iron level and serum siderophyllin, hemogram, reticulocytes, inflammatory tests, hemolysis parameters and hepatic enzymes were evaluated before treatment and around the fourth, twelfth and twenty first day after. Response to treatment was measured in all patients. In each patient, regardless of the sex, nature of the tumor or drugs administered, a high increase of serum-iron level was observed between the third and the seventh day after the start of treatment (mean: +263%, range: 78-953%). In twenty one patients, sideremia overstepped the normal range. This variation of serum iron level was transient and the level of sideremia approached the initial rate when it was measured around the thirteenth day after the start of treatment. This phenomenon did not appear to be related to tumor lysis, hemolysis, liver cytolysis or improvement of the inflammatory syndrome. The constant observation of reduction in reticulocytes concurrent with the increase in serum-iron, suggests a mechanism involving impairment of the reticulo-endothelial cells implicated in iron metabolism, due to anticancer drugs. Among the drugs used in this study, actinomycin D, adriamycin, cyclophosphamide and 5-fluorouracil seem to be imputed in the phenomenon observed.

Copper and zinc concentrations, and superoxide dismutase activities in malignant and nonmalignant tissues of female reproductive organs.

The copper and zinc concentrations in 44 malignant and 48 nonmalignant women tissue samples of reproductive organs in women were measured. In malignant samples, the mean copper concentrations were 110%, 76%, and 38% higher for cervix, endometrium and ovary than the nonmalignant ones. The zinc concentrations in the analysed malignant tissues were lower than that in the corresponding nonmalignant tissues. The results of superoxide dismutase activities determinations demonstrate a considerable lowering of the enzymatic capacities to remove free oxygen radical in malignant tissues. A hypothesis for possible mechanism involving elevated copper concentrations, and decreased zinc concentrations, which may be responsible for malignant processes, are presented.