Estradiol and progesterone receptors in human breast cancer.

The concentration of estradiol and progesterone receptors in tumor cytosol from human breast cancer patients represents an important factor for the selection of patients for endocrine therapy and for the prognosis of the disease. This report presents results obtained by measurement of estradiol receptor in 157 breast tumors by the dextran coated charcoal method in media containing sodium molybdate (102 cases) or glycerol (55 cases). Results obtained when these two reagents were present separately in the assay media were similar, at least when the frequencies of estradiol receptor positive cases and the mean values for estradiol receptor concentrations were compared. Concomitant analyses for estradiol and progesterone receptors were done in 25 primary mammary carcinomas by the method of dextran coated charcoal using single saturating doses of hormones and cytosols obtained in a glycerol containing buffer. The results are discussed in relation with the steroid hormone mechanism of action.

Vitamin A (retinol) level in colon and lung cancer patient sera.

Serum vitamin A (retinol) level was determined in colon and lung cancer patients. As a control served young healthy people and non cancer hospital patients at the age similar to those with tumors. Vitamin A content in cancer patients was found to be statistically lower as compared to control groups.

Factors associated with prognosis in human breast cancer. V. The simultaneous use of estrogen and progesterone receptor measurements for prediction of short-term relapse.

Prediction of individual fate of breast cancer patients is one of the most important subjects studied because of the heterogeneity of the disease and the possibility of establishment of new therapeutic strategies. Hormone receptors have been recognized to be a valuable tool in prognosis at least in regard to short-term relapse. We have analyzed 400 patients in which hormone receptors has been determined, through stratification techniques, in 18-month and 3-year periods of disease-free interval. Clinical stage was chosen at the most important predictor in the total number of patients, lymph node status was the first predictor, estradiol receptor (ER) automatically was the second one, and the amount of receptor content had an important role in prognosis also. Inside Stage III patients ER should be the first predictor. Remarkable and independent association of progesterone receptor (PgR) content with relapse could be established. Predictive ability of ER and PgR inside lymph node status groups of patients was clearly shown. There was a remarkable difference between polar groups (lymph node-negative, ER+PgR+6% of relapse, and lymph node-positive, ER-PgR-30% of relapse) estrogen receptor status retains its predictive value, at the third year.

Survival patterns of female breast cancer patients in the Estonian SSR in 1968-1981.

Survival of 4090 female breast cancer patients in the Estonian SSR in 1968--1981 was studied on the basis of the republic-wide, population-based Estonian Cancer Registry. Using the life table method, the overall estimated 5-year relative survival rate was 55.9%. Survival was related to stage of disease and patient's age at diagnosis. Breast cancer, the most frequent malignancy in females in Estonia, considerable reduces patient's life expectancy. During the entire 13-year follow-up period the patient population under study experienced excess cancer mortality.

End results of treatment of breast cancer patients.

Data are presented on 3359 breast cancer patients treated at the Petrov Research Institute of Oncology of the USSR Ministry of Health. For the 20-year period (from 1955 to 1975) not large but statistically significant increase of the 5-year survival was noted which achieved 64.7% in 1971-1975. The rise of survival was observed in patients aged under 50, subjected to adjuvant chemotherapy (Thio-TEPA, 5-Ftoruracil). Development of distant metastases was the cause of death of breast cancer patients within the 15 years after the beginning of treatment in 68.8% of cases. Only 7.6% of patients expired from distant metastases in 15-20 years following operation.

Epidemiologic aspects of malignant skin melanoma in Slovakia.

The trends of age-adjusted incidence rates of malignant skin melanoma in Slovakia from 1968 to 1977 showed important increase with an annual increment of 5.8% in males and 3.2% in females. The mortality rates during this period remained lower and their increase was less expressed. The study of geographic patterns of incidence revealed great variation with highest rates in urban districts. A marked predominance of the primary lesions on trunk in males and on lower limbs in females was observed. The differences in anatomic distribution are demonstrated also in age-specific incidence rates of malignant skin melanoma by main subsites. Intermittent overexposures to the sunlight in connection with rising standard of life and leisure seem to be the most suitable explanation for the rise and subsite distribution and dynamics, as well as the geographic patterns and international position of incidence rates of malignant skin melanoma in this country.

Potential anticancer agents--nitroxyl derivatives of Rubomycin.

Two new of the spin-labeled analogues of Rubomycin were studied. It was shown that spin-labeled derivatives were less toxic than the parent compound and had a broad-spectrum antitumor activity. Spin-labeled derivative was clearly less cardiotoxic in the rat model than Rubomycin (Daunorubomycin).

Enhanced utilization of 14-methylhexadecanoic acid for the synthesis of lipids during the growth of Walker 256 carcinoma in rats.

Labeled 14-methylhexadecanoic acid was administered to normal rats, animals bearing the Walker 256 tumor at various stages of its growth and to tumor-resistant rats and its distribution in lipids (free fatty acids, triglycerides, phospholipids and cholesteryl esters) was studied during 15 min to 3 hours following its injection in the liver, blood and tumor tissue. The period of the most active tumor growth was associated with a significantly better utilization of this fatty acid for the synthesis of lipids. The quantities of radioactive triglycerides, phospholipids and cholesteryl ester in the liver were highly increased during this time. In tumor-resistant animals the levels of radioactive lipids were similar to those in control normal animals but the turn-over of 14-methylhexadecanoic acid was considerably slower than in controls. The turn-over of the cholesteryl 14-methylhexadecanoate in the liver was significantly changed at the late stages of the tumor growth. The level of this cholesteryl ester in the blood decreased progressively during the tumor growth whereas that of triglycerides increased. No significant changes were associated with the free fatty acid and phospholipids in the blood. The total radioactivity present in the tumor increased from 0.05% up to nearly 1% of the administered 14-methylhexadecanoic acid during the growth of the Walker 256 tumor. The level of radioactive cholesteryl 14-methylhexadecanoate in the tumor tissue increased progressively during 3 hours following the injection of 14-methylhexadecanoic acid. Thus the tumor growth is apparently accompanied by significant changes in the metabolism of 14-methylhexadecanoic acid and results in an enhanced synthesis of lipids in the liver tissue. The newly synthesized lipids, in particular cholesteryl 14-methylhexadecanoate, are transported in the blood stream into the tumor where they accumulate.

Flow cytometry of radiation-induced tumors in rats.

Hundred sixty female Wistar rats were total-body irradiated with 4 Gy gamma rays. Mammary gland tumors started to occur 8 months after irradiation, beside that also tumors of different sites appeared. By flow cytometry (FCM) 30 tumors were examined: mammary gland--22, skin--4, adrenal gland--2, liver--1, thymus--1. Eight tumors were characterized as malignant and 22 as benign. All benign and 6 malignant tumors were composed of diploid cells only. In 2 carcinomas together with diploid cells aneuploid cell lines were also found. DNA index (DI) of aneuploid cells in both carcinomas (1 mammary gland and 1 adrenal gland) indicated values of 1.66 and 1.68, respectively. Most cells of the benign and the malignant tumors occupied G1/0 (79-94%) phase of the cycle. The fraction of S (4.1-14.3%) and G2M (0.5-7.7%) cells was relatively small that suggests a low proliferative activity of radiation-induced tumors.

Effects of sodium nitrite and potassium sorbate on in vitro cultured mammalian cells.

The food additives sodium nitrite and potassium sorbate had cytostatic and cytotoxic effects on in vitro cultured V79 hamster cells and EUE human fibroblasts if administered in an acid environment (pH 4.95). The strong cytotoxic effect of sodium nitrite and that of the combined action of sodium nitrite and potassium sorbate was observed along the inhibition of macromolecular synthesis. In this respect, potassium sorbate was less effective. The decreased plating efficiency of the cells and the inhibition of de novo DNA synthesis induced by these substances aroused the question whether they also have genotoxic effects on V79 cells. Statistical analyses showed that sodium nitrite induced more 6-TG-resistant (6-TGr) mutants as compared to the untreated control. However, this elevation did not correspond to the level of inhibition of DNA synthesis determined during the followed period of time after the removal of the substance. Potassium sorbate and a combination thereof with sodium nitrite, in our experiments, had no mutagenic effects.

Giant cell formation in cultured L5178Y lymphoblasts induced by hydroxyurea treatment.

The conditions leading to hydroxyurea-induced abnormal cell enlargement (giant cell formation) were studied in L5178Y lymphoblasts in the culture. Exposure for only 1 hour to a concentration of 1 mM hydroxyurea (HU) was sufficient to produce an abnormal enlargement of about 25 percent of the cells. The maximal proportion of giant cells reached the value of about 50 percent after treatment with 1 mM HU for 5 hours and was not changed by a further prolongation of exposure time and/or by increasing the concentration of HU to 10 mM. Comparison of cell populations with various proportions of giant cells as regards their ability to reproduce, DNA synthesis and persistence in the culture suggested that at least some part of giant cells lost the ability to divide, their DNA synthesis was markedly suppressed or retarded and more than 50 percent of them disappeared earlier than 48 hours after the termination of HU exposure. It is concluded that at least at certain HU concentrations and in suitable stage of target cells the response of cells to short HU treatment can resemble that produced by X-rays or other DNA damaging agents.

Cytogenic analysis of transplantable mouse B16 melanomas.

The cytogenetic analysis of transplantable in vivo melanotic and amelanotic lines of mouse B16 melanoma was performed. The second line arose by spontaneous alteration of the first one and these lines are the same in the rate of malignant growth during passages in vivo. The melanotic line shows stable near-diploid karyotype with modal chromosome number 41. The amelanotic line is mostly hypotetraploid karyotype with modal chromosome number 76. The balance of the diploids in the melanotic line is disturbed by the fact that chromosome 15 is partially trisomic, chromosome 6 trisomic, and chromosome 13 and X monosomic. Four marker chromosomes were common to both lines: M1-rob(12;12), M2-rob(5;15), M3-minute, M4-inv(1), M5-del-(14q-), but in the amelanotic line in most cases their number was doubled. Additionally, in the amelanotic line other specific aberrations rob(6;6) and rob(16;16) were observed. Both lines had comparable SCE frequencies. Constitutive heterochromatin in amelanotic line revealed the nonrandom deletion of the heterochromatic segments in chromosome 11 and, occasionally in chromosome 19.

Intracellular ionic changes during hyperthermia of tumor cells in the presence of lanthanum.

The experimental data suggest that permeability changes at the plasma membrane level are the most likely cause of the enhancement of tumor cell killing by hyperthermia in the presence of 1 mM La3+. The interaction of La3+ with the Na+, K+ ATPase and Ca2+-pump ATPase may be the probable cause of dramatic electrolyte changes which enhance the hyperthermia effects on tumor cells.

Antitumor activity of sarcolysin containing crosslinked copolymers in mice.

Some years ago it was found that the binding of sarcolysin to the copolymer of vinylpyrrolidone and maleic anhydride results in changes of some its pharmacological properties including toxicity, antitumor activity and immune suppression. In an attempt to keep some of this qualities of the polymeric derivatives of sarcolysin and to develop a depot-effect, sarcolysin was bonded to space linked insoluble copolymers. Studies carried out on the antitumor action in 6 transplantable tumors (L1210, P388, EAT, NK/Ly, LLC and Sarcoma 180) are discussed.

The antitumor activity of oxoplatinum.

A coordination complex cis-dichlorodiamminedihydroxoplatinum (IV) (oxoplatinum) was first synthesized in the USSR by Chugaev and Khlopin in 1927 [3]. Its marked antitumor properties were revealed by one of the authors of this article at the All-Union Cancer Research Center of the Academy of Medical Sciences of the USSR. The paper gives data on the antiblastic and side effects of oxoplatinum and also on the results of pharmacokinetic studies of the drug. Particular attention was paid to the similarity and differences of biological properties of oxoplatinum and cis-dichlorodiammineplatinum(II) (DDP) which has found wide use in oncological practice. It has been established that, on principle, oxoplatinum differs from DDP in action on the body and tumors. The new drug is 10 times less toxic than DDP. Oxoplatinum has a wide spectrum of antineoplastic action resulting in marked inhibition of growth of solid and ascitic forms of transplantable tumors. The drug has a longer duration of antitumor effect after the end of the therapeutic course. An important property of oxoplatinum is its high therapeutic index. The new drug manifests high antitumor activity with different ways of its administration into the body. Oxoplatinum in therapeutic doses does not produce necrotic lesions in the kidneys. The new drug exerted no cross-resistance with DDP and the alkylating antitumor agent sarcolysin. At the present time oxoplatinum is undergoing preclinical investigation.

Effect of cis-diamminedichloroplatinum (II), cyclophosphamide and tumor age on the rate of mitochondrial and overall cellular protein synthesis in Zajdela hepatoma.

The effect of in vivo treatment with cis-Pt(II) and/or cyclophosphamide on overall cellular and mitochondrial protein synthesis in Zajdela hepatoma was examined. The rate of the overall cellular protein synthesis decreased by about 60-80%, whereas the rate of the process in mitochondria was affected only marginally upon the treatment. Qualitatively similar changes in the relative rates of the two processes were found in Zajdela hepatoma cells during the ageing of the tumor.

Ototoxicity of cis-diamminedichloroplatinum.

In 19 evaluable cancer patients treated with cis-diamminedichloroplatinum (cis-DDP) Platidiam-Lachema containing chemotherapy the ototoxicity was assessed. There was an increase of hearing threshold of air-conduction in frequency of 6000 and 8000 Hz as compared with pretreatment audiograms in four patients (21%). In one case only the hearing loss was reversible. The usual hearing loss was of 10--15 dB and maximal of 20 dB. In those four patients with ototoxicity the decrease of creatinine clearence under 60 ml/min occurred at the same time. It is suggested that the altered renal function could be a cause of cis-DDP level rise in body liquids and in this way a cause of further more severe side effects. Neither subjective hearing loss nor tinnitus nor otalgia was found. The cis-DDP caused high frequency hearing loss but has not affected the correct speech percept. To avoid serious cis-DDP ototoxicity it is necessary to monitor renal functions and audiograms carefully and to administer cis-DDP slowly in chloride-containing vehicles after sufficient prehydratation.

A simple technique for cell surface radioactive labeling of human and animal neoplastic cells: reductive methylation with formaldehyde and tritiated borohydride.

Avian sarcoma virus-, or 3,4-benzopyrene-transformed cultured rat cells and human leukemia or lymphoblastoid cell lines were radiolabeled by reductive methylation with formaldehyde and tritiated sodium borohydride--an application of a known technique for radiolabeling of soluble proteins. Optimal conditions for tritium incorporation into cell proteins with the aid of this technique were ascertained. Analysis of cell proteins tritium radiolabeled with the aid of this technique by acrylamide electrophoresis or by two-dimensional electrophoretic analysis allowed to disclose typical transformation-associated alterations in oncovirus-, or chemical carcinogen-transformed cells, as well as cell type-associated protein patterns in examined lymphoid cell lines. An individual protein (class II MHC antigen) radiolabeled by this technique has been identified as bimolecular complex p30,35 by immunoprecipitation with a monoclonal antibody recognizing this antigen; electrophoretic properties of immunoprecipitated antigen were identical to those observed after immunoprecipitation of the same antigen radiolabeled by sodium periodate/tritiated borohydride glycoprotein radiolabeling.

The effect of zinc on mouse melanoma growth in vitro and in vivo.

The effect of Zn2+ on mouse melanoma growth in vitro and in vivo was studied. Under in vitro conditions the proliferation of a Cloudman mouse melanoma cell line was inhibited by zinc ions at 10(-4) M, as measured by 3H-thymidine incorporation and optical density of NaOH cell digests. However, in vivo it was not possible to suppress both B16 and Cloudman S91 melanoma growth in mice by the administration of zinc ions. There were no significant differences in tumor growth after subcutaneous inoculation between mice constantly receiving 0.1% zinc acetate or 0.05% zinc sulphate in their drinking water and control groups, nor was it possible to decrease the number of lung metastases by zinc treatment after intravenous inoculation of tumor cells. The increased dietary supply of Zn failed to influence the survival time of mice in both melanoma types studied. Preincubation in vitro of cell suspensions in 10(-3) M zinc acetate prior to injection inhibited melanoma development in vivo. This implies that the in vivo zinc levels did not reach the necessary cytotoxic concentration.

The use of protein as a carrier of methotrexate for experimental cancer chemotherapy. I. Preparation of pea seed lectin-methotrexate derivative and the preliminary experiments.

A method of preparation of pea seed lectin-methotrexate derivative by means of hydroxy-succinimide ester of methotrexate was elaborated. Five moles of methotrexate was bound to one lectin mole on the average as verified by analysis. For the distribution study lectin was labeled with 131I. Labeled lectin was administered intravenously to Yoshida sarcoma bearing rats and its distribution in the organism was monitored. After 24 hours the labeled lectin was entrapped predominantly in the reticuloendothelial system but after 48 and 72 hours the accumulation was seen also in thyroid, urinary bladder and tumor (1/4 cases only). The discrepancy in distribution of lectin in the tumor has been discussed.

Effect of BCNU, administered to pregnant female rats, on morphology and histochemistry of brain neurocytes in the progeny.

For evaluation of neurotoxicity of 1,3-bis[2-chloroethyl]-1-nitrosourea (BCNU) effects of the compound were examined on histoenzymatic activity of some phosphatases and esterases and on karyometry and DNA cytophotometry in brain neurocytes of the progeny of mothers who had been given the drug during pregnancy. The studies were performed on young, 14 and 28 days old rats of Wistar strain originating from mothers given intraperitoneal BCNU injections on the 12th and 18th day of pregnancy. Material of the studies included neurocytes of frontal cortex, parietal cortex and of trigeminal nerve nucleus in which enzymatic activities of some phosphatases and esterases were estimated and which were subjected to karyometric and DNA cytophotometric measurements, using Morphoquant automated microscopic image analyzer (VEB Carl Zeiss, Jena). The experiments documented decreased nonspecific esterase and ATPase activities and increased activities of acetylcholinesterase, cholinesterase, alkaline phosphatase and acid phosphatase in neurocytes of experimental animals, as compared to control animals of the corresponding age. The changes were noted both in 14 and 28 days old animals. Changes in thiamine pyrophosphate phosphohydrolase (TTPase) enzymatic activity were of different type in dependence upon age of the animals (increased activity in 28 days old rats, decreased activity in 14 days old rats). In animals subjected to BCNU action in fetal life several karyo- and cytophotometric changes were noted also: circumference and area of cell nuclei cross-sections were decreased, cell nuclei became more round, relative DNA content of cell nuclei increased with parallel increases in compactness and concentration of nuclear chromatin. Karyometric changes showed similar character in both age groups while changes in DNA cytophotometry were more evident in 14 days old rats.

Enhancing effect of quercetin on 3-methylcholanthrene carcinogenesis in C57Bl/6 mice.

We investigated the effect of quercetin on 3-methylcholanthrene (MCA) carcinogenesis in C57Bl/6 mice. We found that quercetin itself was not carcinogenic when administered i.m., even at a dose of 20 mg, throughout an observation period of 420 days. An i.m. administration of various doses of quercetin admixed with 1.0 mg of MCA, however, significantly shortened the mean latency periods for the development of local primary tumors compared with those of the group which had been given MCA alone. The shortening of latency periods was also found in the experiments using 0.1 mg of MCA after the administration of quercetin either admixed with MCA or fed with a diet containing it. Moreover, lung metastasis increased in mice given the mixture of MCA (0.1 mg) and quercetin compared with its occurrence in mice given MCA alone. A simultaneous administration of MCA and quercetin significantly increased the in vivo sister chromatid exchanges (SCE) formation of bone marrow cells when compared with its occurrence in the group given MCA alone. These results suggest that quercetin has an enhancing effect on MCA carcinogenesis and that this enhancement may be associated with such a genetic effect as an increased mutation rate in the host.

Immune response of mice to sarcoma I allograft studied by adoptive transfers of spleen, thymus, and lymph node cells to secondary recipients.

Thymus, spleen, and lymph node cells from different periods of Sarcoma I allograft development in untreated (Sa I) or xenogeneic antithymocyte serum-treated (ATS-Sa I) B10 mice were adoptively transferred to secondary B10 recipients. While in sublethally (4.3 Gy) irradiated recipient mice the tumor destructing activity was predominantly expressed, in untreated recipients of transferred cells it was mostly the tumor enhancing activity. Therefore, in further studies directed at the detection of tumor enhancing activity, the adoptive transfers were only performed in untreated recipients. Thymus cells both of Sa I and ATS-Sa I mice showed a tumor enhancing activity all through the followed period, with a peak between days 7 and 21, then it decreased. Also the spleen cells of both groups had a tumor enhancing effect all the time, with a peak of activity on day 7. Spleen and thymus cells of progressors enhanced the tumor growth slightly more strongly than did those of the regressors. The tumor enhancing activity of spleen cells was in the beginning period confined mainly to the polystyrene nonadherent fraction of cells, at later times, in the progressors it was manifested in the adherent as well as in the nonadherent fractions. In the population of lymph node cells, at the start of tumor regression (in Sa I mice on day 7, in ATS-Sa I mice on day 14), a tumor destructing activity was observed. In both groups this activity was at later times followed by a tumor enhancing activity. The interpretation of the tumor enhancing activity of thymus and spleen cells of Sa I and ATS-Sa I mice is complicated by the tumor enhancing activity of cells of normal mice without tumor (N).

Study of the role of steroid receptors in human breast cancer.

Cytoplasmic estrogen receptors (ER) were studied in 200 female patients with primary breast cancer. Both ER and progesterone receptors (PgR) were studied in 38 patients. Of the 200 tumors, 55% were estrogen receptor-positive, of the 38 tumors, 34.2% were progesterone receptor-positive. The level of steroid receptors was compared with some parameters characterizing the host and the tumor. It was found that the level of ER correlated with the age factors and the menstrual status. The level of ER was higher in women with adrenal or involutive pathogenetic forms of breast cancer and in women with great body weight. There was not found any relation between the level of estrogen receptors and the stage of menstrual cycle as well as between the level of estrogen receptors and the content of sex chromatin in the tumors.

Prognostic significance of stratification systems in multiple myeloma. I. Risk categories (good and poor risk).

A group of 193 patients with multiple myeloma (MM) consisting of cases treated only symptomatically or by nonsystematic therapy with Cyclophosphamide or Melphalan (1959-76), and of patients given systematic polychemotherapy with intensive supportive treatment (1976-84) were subjected to prognostic analysis of the importance of MM stratification into two categories, poor and good risk. The evaluation included only hitherto untreated patients with MM of the IgG, IgA, and Bence-Jones' types. All the three evaluated stratification systems (ALGB, NCI-SECSG and CALGB) were found in the present study to show a good, equally significant relation to the prognosis of the disease. The survival median of poor risk patients in terms of the used classification system for the 1959-76 subgroup was 5-6 months, for the 1976-84 subgroup 20-22 months. In the good risk category it was 24-27 months in the 1959-76 subgroup and 47-50 months in the 1976-84 subgroup. Permanent validity of the initial prognosis and in the poor risk category safe coverage of patients with a high risk of early death was proved. Good agreement of the studied stratification systems with the clinical staging system of Durie and Salmon [14] (most of the Stage III patients consisted of poor risk patients) was recorded, which, however, was not the case with the staging system of Merlini, Waldenström and Jayakar [27]. The CALGB system is considered the most suited to the needs of clinical practice.

Prognostic significance of stratification systems in multiple myeloma. II. Clinical staging systems.

A group of 193 multiple myeloma (MM) patients consisting of cases treated only symptomatically (1959-63) or by nonsystematic monotherapy with Cyclophosphamide or Melphalan (1963-76) and of a subgroup given systematic polychemotherapy and intensive supportive treatment (1976-84) were evaluated for the practical applicability and prognostic relevance of three staging systems. The clinical staging system of Durie and Salmon and the quantitative system of Salmon and Wampler have proved in both subgroups of various periods and with different therapeutic approaches to be well applicable in the clinic allowing the patients to be divided into three prognostically different groups according to the size of the tumor mass. Merlini, Waldenström and Jayakar's staging system has likewise shown relationship to prognosis though the patients could be divided only into two prognostically different groups. It is evident that a deeper knowledge of MM requires nowadays a more comprehensive, complex and prognostically more relevant classification system.

Secondary tumors in cancer patients after therapy.

Forty-five thousand three hundred thirteen patients treated in our Institute during the period 1949-1982 were retrospectively analyzed in regard to the appearance of secondary tumors after therapy. Eighty-seven (0.19%) tumors were found, 71 (81.6%) being secondary and 16 (18.4%) simultaneous. Fifty-one (71.8%) tumors were lymphoid, 20 (28.1%) nonlymphoid. Thirty-seven (52.1%) tumors appeared after radiotherapy, 13 (18.3%) after chemotherapy alone. Secondary tumors appeared mostly after 6 years. The prevalence of lymphoid secondary tumors may be explained as a compensatory proliferation of surviving cells progressing to neoplasia. Cytostatics and ionizing radiation as both the initiators and the promoters of malignancy, have besides person's susceptibility a triggering function. From these aspects before any treatment is started all possible carcinogenic factors should be taken into consideration and less carcinogenic procedures with keeping up a full effectiveness should be chosen.

High-dose metoclopramide in the treatment of cis-platinum induced emesis. A dose-finding study.

In 92 patients receiving 270 cytostatic courses which all included cis-platinum, the antiemetic efficacy of medium- or high-dose metoclopramide was investigated. Metoclopramide was given intravenously 4 times during a 6-hour period (1/2 h before and 1 1/2, 3 1/2 and 5 1/2 h after cytostatic treatment) in a total dose of 1, 2, 4, 6, or 8 mg/kg. Nausea, emetic episodes, and side effects were registered during 24 h. The 1 mg/kg dose was given in 20 courses for which the average of emetic episodes was 16. In the four higher dosed groups the averages were 8, 8, 5, and 6, respectively. The average number of emetic episodes was significantly higher (p less than 0.001) in the 1 mg/kg metoclopramide group than in the 250 higher dosed courses. The frequency of side effects seemed independent of the dose in the interval 2-8 mg/kg while diarrhoea and other side effects tended to be less frequent in the 1 mg/kg metoclopramide group. Since antiemetic effect of metoclopramide in the dose interval 2-8 mg/kg did not increase with the dose, it is recommended to treat cis-platinum-induced emesis with 2 mg/kg metoclopramide given intravenously as 4 doses during a 6-hour period.

Is there an increased risk of colorectal cancer after cholecystectomy?

The incidence of cholecystectomy was not higher in 525 colorectal cancer patients than in subjects without colorectal cancer of the same age and sex living in the same region. If we did not include the persons who underwent cholecystectomy 1 or 2 years before the diagnosis or the examination was made, the number of cholecystectomy patients was the same in both groups. Right-sided and left-sided localizations of colon cancer after cholecystectomy did not differ from those without cholecystectomy. The tendency to right-sided colon cancer in women who have undergone cholecystectomy was not significant. Patients after cholecystectomy have no higher risk of colorectal cancer than persons without cholecystectomy.

Drug action and chromatin structure. I. Adriamycin binding to core particle of nucleosomes and subsequent enhanced DNA fragmentation induced by micrococcal nuclease.

The relevance of the subunit structure of chromatin to the mode of action of Adriamycin in Novikoff hepatoma had been investigated. To elucidate whether drug binding takes place at random along the chromatin fiber or not Novikoff hepatoma nuclei treated with Adriamycin in vivo were digested with Micrococcal nuclease and were subsequently separated into three fractions, S1, S2 and P2. In these chromatin fraction Adriamycin and the DNA content was determined. DNA were isolated from the above fractions and were analyzed by polyacrylamide gel electrophoresis, furthermore the S2 fraction was sedimented on sucrose density gradient. The results indicate that binding of Adriamycin takes place preferentially on the core particle inducing structural alterations. Adriamycin binding not only enhanced DNA nuclease digestion but altered the size of the fragments.