Showing papers in "Journal of Cancer Research and Clinical Oncology in 1984"
TL;DR: The ferricenium compounds are the first iron complexes for which antineoplastic activity has now been shown, and represent a new type of antitumor agent insofar as they differ fundamentally from known inorganic and organometallic antitumors.
Abstract: The antitumor activity of a series of iron complexes, i.e., of ferrocene [Cp2Fe], of tetrachloroferrates(III) [R4N]+[FeCl4]-, and of ferricenium complexes [Cp2Fe]+X- (X- = [FeCl4]-, 1/2 [Cl3FeOFeCl3]2-, [H5Mo7O24]- X 2H2O, [2,4,6-(NO2)3C6H2O]-, or [CCl3COO]- X 2 CCl3COOH) was investigated against EAT in CF1 mice. Whereas ferrocene and the ammonium tetrachloroferrates(III) did not show recognizable tumor-inhibiting activity, such activity was exhibited by the water-soluble, salt-like ferricenium complexes; the best antineoplastic properties, with optimum cure rates of 100%, were found for ferricenium picrate and ferricenium trichloroacetate. The ferricenium compounds are the first iron complexes for which antineoplastic activity has now been shown. They represent a new type of antitumor agent insofar as they differ fundamentally from known inorganic and organometallic antitumor agents (a) by their ionic, salt-like character, which is responsible for their high water solubility, and (b) by the absence of a cis-dihalometal moiety; this moiety has been recognized as important for the intracellular action of other known inorganic cytostatics.
214 citations
TL;DR: Bioassays at lower dose levels as well as biochemical studies are strongly indicated for NNN and NNK since these nitrosamines occur in relatively high amounts in both chewing tobacco and tobacco smoke.
Abstract: Tobacco and tobacco smoke contain relatively high amounts of four tobacco-specific N-nitrosamines. Of these, N-nitrosonornicotine (NNN), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), and N′-nitrosoanatabine (NAT) were bioassayed at three dose levels by subcutaneous injections into male and female F344 rats in 60 subdoses amounting in total to 9, 3, and 1 mmol/kg. Compared with the solvent control group (trioctanoin), both NNN and NNK induced significant numbers of tumors of the nasal cavity (P<0.01) at all three dose levels in both male and female rats. Significant numbers of tumors were also induced by NNK in the lung at all three dose levels and in the liver at the highest dose level (P<0.05). In addition to nasal tumors NNN also induced esophageal tumors at a significant rate in male rats at the high and medium dose levels and in female rats at the high level (P<0.05); NAT was inactive at the three doses tested. Bioassays at lower dose levels as well as biochemical studies are strongly indicated for NNN and NNK since these nitrosamines occur in relatively high amounts in both chewing tobacco and tobacco smoke.
123 citations
TL;DR: In gastric cancer patients with marked serosal invasion, intraoperative IP administration of cytocidal anticancer drugs should be considered, because peritoneal metastasis was the most frequently observed recurrence pattern.
Abstract: We performed intraoperative peritoneal cytology in 171 gastric cancer patients undergoing curative surgery. Intraperitoneal free cancer cells were demonstrated in almost all patients in whom the area of serosal cancer invasion exceeded 15–20 cm2. In patients with both serosal cancer invasion and free cancer cells the 5-year survival rat was 13% as compared with 85% for patients who had neither, and 40% for patients who had serosal invasion but no free peritoneal cancer cells. Peritoneal metastasis was the most frequently observed recurrence pattern. There-fore, in gastric cancer patients with marked serosal invasion, intraoperative IP administration of cytocidal anticancer drugs should be considered.
123 citations
TL;DR: The results have been improved with modern combination chemotherapy, which includes cisplatin, although a longer follow up is needed for definite conclusions to be made concerning survival.
Abstract: The chemotherapy of advanced ovarian cancer is reviewed. Treatment with single agents results in low remission rates and few complete remissions. The results have been improved with modern combination chemotherapy, which includes cisplatin, although a longer follow up is needed for definite conclusions to be made concerning survival. Toxicity and drug resistance remain important problems. The future prospects of treatment with emphasis on intraperitoneal chemotherapy are discussed.
117 citations
TL;DR: The age incidence of patients with ovarian carcinoids shows a wide range but most patients are postmenopausal, and should be treated as ovarian tumors of low malignant potential.
Abstract: Carcinoid tumors of the ovary are uncommon, but 150 cases of primary ovarian carcinoids and 40 cases of carcinoid tumors metastatic to the ovary have been reported.
83 citations
TL;DR: This article found N-nitrosoguvacoline in the saliva of betel-quid chewers (2.2-350 ppb) when the quid contains tobacco, N′-nitrosonornicotine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (1.0-2.3 ppb), and N′-(nitrosoanatabine) (3.2−39.5 ppb).
Abstract: Betel quid chewing is strongly associated with cancer of the oral cavity, especially when tobacco is added to the quid. It is our working hypothesis that, during chewing, Areca-derived N-nitrosamines are formed and, in the presence of tobacco, Nicotiana-specific N-nitrosamines are formed as well and further that these agents may contribute to the high risk of oral cancer in betel-quid chewers. This preliminary report presents our finding of N-nitrosoguvacoline in the saliva of betel-quid chewers (2.2–350 ppb). When the quid contains tobacco, the tobacco-specific N-nitrosamines, N′-nitrosonornicotine (1.2–38.3 ppb), N′-nitrosoanatabine (3.2–39.5 ppb), and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (1.0–2.3 ppb) are also found in the saliva.
77 citations
TL;DR: Modifying effects of age, sex, and mouse strain on diethylnitrosamine (DEN) carcinogenesis have been investigated in C57BL/6Jx C3HeB/FeJ F1 (B6C3F1) and C3 he/she hybrid mice, finding that animals treated as newborns and infants developed significantly more liver tumors than animals that were treated as young adults.
Abstract: Modifying effects of age, sex, and mouse strain on diethylnitrosamine (DEN) carcinogenesis have been investigated in C57BL/6Jx C3HeB/FeJ F1 (B6C3F1) and C3HeB/FeJxA/J F1 (C3AF1) hybrid mice Animals each received four IP injections of 15 or 30 μg DEN/g body weight The first injections were administered on days 1, 15, or 42 of life Subsequent treatments were delivered at 3-, 6-, and 6-day intervals, respectively Mice were kept under observation for the remaining life-span DEN treatment induced tumors in liver, lungs, and forestomach in descending order of frequency The majority of the induced liver tumors were hepatocellular carcinomas Animals treated as newborns and infants developed significantly more liver tumors than animals that were treated as young adults Newborn and infant females developed liver tumors at a later age (B6C3F1) and with a lower incidence (C3AF1) than similarly treated males The B6C3F1 mice developed more hepatocellular carcinomas and a higher rate of pulmonary metastases than the C3AF1 mice In contrast, C3AF1 mice developed lung tumors with a higher incidence and multiplicity than B6C3F1 hybrids Forestomach tumors were observed also with a slightly but significantly higher incidence in C3AF1 mice
73 citations
TL;DR: Clinical aspects of 145 cases of nodular paragranuloma (nodular subtype of lymphocyte predominance type of Hodgkin's disease) were investigated, and there was a marked male predominance.
Abstract: Clinical aspects of 145 cases of nodular paragranuloma (nodular subtype of lymphocyte predominance type of Hodgkin's disease) were investigated. There was a marked male predominance, and the age curve showed a peak in the 4th decade. In a majority of cases lymphadenopathy developed within 1 year. General (B) symptoms were observed in only 15 patients. The most frequent sites of primary involvement were cervical, axillary, and inguinal lymph nodes. Other organs were rarely involved. At the time of diagnosis 50% of patients were in stage I, 21% in stage II, 22% in stage III, and 7% in stage IV. The prognosis was usually favorable or very favorable and depended on the stage of disease at diagnosis and on the age of the patient. Patients with stage I or III disease without splenic involvement had about the same probability of survival as the normal population. Stage III patients with splenic involvement had a lower probability of survival. The prognosis for stage II was also less favorable. Patients in stage IV had the lowest probability of survival. Closer analysis of the ten stage IV cases revealed two groups with different outcomes. Four cases showed progressive disease that did not respond to treatment and led to death within 12 months. The second, more favorable form (6 patients) responded well to chemotherapy. Nine patients in stage I who were not treated after lymph node biopsy were free of disease even after periods of up to 14 years. A total of 52 patients had one or more relapses. The recurrent tumors developed locally in a majority of cases. There was transformation of nodular paragranuloma into another subtype of Hodgkin's disease in only four cases. Five cases showed transformation into large-cell tumors that resembled immunoblastic lymphoma and require further immunological study.
72 citations
TL;DR: Results of the cytochemical and biochemical microanalysis of preneoplastic hepatocytes support the concept that the well-known aberration of carbohydrate metabolism in tumor cells might occur in response to a carcinogen-induced metabolic derangement, which frequently appears to be associated with an excessive storage of polysaccharides or lipids persisting for weeks and months until fast-growing tumors develop.
Abstract: Phenotypically altered, preneoplastic cell populations were detected by micromorphological and cytochemical methods in a number of tissues treated with various chemical carcinogens. Further cellular analysis of carcinogenesis has shown that different cellular phenotypes follow each other during tumor development. Thus, stages of the neoplastic transformation leading from preneoplastic to early and advanced neoplastic cells can be observed directly. The cellular changes preceding the various tumor types suggest that cytologically different neoplasms have also a different cytogenesis. The identification of putative preneoplastic and early neoplastic cell populations by morphological and cytochemical methods allows for the first time the dissection and subsequent detailed investigation of target cells of chemical carcinogens that are at high risk of becoming cancer cells. Recent results of the cytochemical and biochemical microanalysis of preneoplastic hepatocytes support the concept that the well-known aberration of carbohydrate metabolism in tumor cells might occur in response to a carcinogen-induced metabolic derangement, which frequently appears to be associated with an excessive storage of polysaccharides or lipids persisting for weeks and months until fast-growing tumors develop. The increasing reports on the appearance of hepatic tumors in humans suffering from inborn hepatic glycogenosis agree with this hypothesis. Whereas the cause of the persisting storage phenomena is most probably fixed at the genetic level, epigenetic changes, namely an adaptation of cellular enzymes gradually activating alternative metabolic pathways, might be responsible for the ultimate neoplastic transformation of the cell.
72 citations
TL;DR: A highly sensitive immuno-slot-blot procedure that can be routinely applied for detection and quantitation of any heat- or alkali-stable structural DNA modification (caused by carcinogens or mutagens, for example) for which a specific (monoclonal) antibody (MAB) is available.
Abstract: We have established a highly sensitive immuno-slot-blot (ISB) procedure that can be routinely applied for detection and quantitation of any heat- or alkali-stable structural DNA modification (caused by carcinogens or mutagens, for example) for which a specific (monoclonal) antibody (MAB) is available. The essential step in this assay is the immobilization on nitrocellulose filters of the structurally modified DNA in its single-stranded form. The immobilized DNA is first reacted with an MAB specifically directed against a particular modified DNA component (e.g., an alkyldeoxynucleoside), and thereafter with a second antibody directed against the first one. The second antibody can be either labeled with 125I or linked to an enzyme complex capable of eliciting a color reaction with a suitable substrate. The sensitivity of the ISB is demonstrated for two different alkyldeoxynucleosides, O6-ethyldeoxyguanosine (O6-EtdGuo) and O4-ethyldeoxythymidine (O4-EtdThd), both of which are produced in cellular DNA exposed to the alkylating N-nitroso carcinogen N-ethyl-N-nitrosourea and both of which represent DNA lesions miscoding during DNA replication and transcription. Using anti-(O6-EtdGuo) and anti-(O4-EtdThd) MABs, respectively, O6-EtdGuo and O4-EtdThd are detected at levels as low as ≧0.3×10-15mol O6-EtdGuo/3 μg DNA (O6-EtdGuo/deoxyguanosine molar ratio in DNA, ≧2×10-7) and ≧0.1×10-15 mol of O4-EtdThd/3 μg DNA (O4-EtdThd/deoxythymidine molar ratio in DNA, ≧4×10-8).
67 citations
TL;DR: Only a number of thiol compounds were suitable for selective regional detoxification and for the prevention of oxazaphosphorine-induced urotoxic lesions.
Abstract: A number of thiol compounds have been studied with reference to their selective protective action against urotoxic side-effects of oxazaphosphorine cytostatics. The uroprotective capacity is determined exclusively by the pharmacokinetic behavior of the compound. When given PO, all compounds tested were absorbable from the gut. Both thiols and disulfides are rapidly eliminated from the blood, but during their short half-life a number of unknown chemical reactions probably take place to maintain a physiological redox equilibrium.
TL;DR: The potent tumor-promoting activity of lyngbyatoxin A is reported for the first time and also the histological examination of tumors are reported.
Abstract: A strong skin irritant, lyngbyatoxin A, isolated from the marine blue-green alga Lyngbya majuscula is structurally related to teleocidin. Since lyngbyatoxin A statisfied our short-term screening tests for possible tumor promoters, viz. irritation of mouse ear, induction of ornithine decarboxylase (ODC) in mouse skin, and adhesion of human promyelocytic leukemia cells (HL-60), a two-stage carcinogenesis experiment was carried out. Tumor incidences in the groups treated with 7,12-dimethylbenz(a)anthracene (DMBA) plus lyngbyatoxin A and with DMBA plus 12-O-tetradecanoylphorbol-13-acetate (TPA) were 86.7% and 93.3% in week 30, respectively. The average number of tumors per mouse was 3.7 in the former group and 10.5 in the latter group. This paper reports for the first time the potent tumor-promoting activity of lyngbyatoxin A and also the histological examination of tumors.
TL;DR: The results are discussed and compared with other published data on NDEIA in cosmetics, with reference to potential human exposure and to possible preventive measures.
Abstract: Commercially available cosmetics and toiletries were analyzed for contamination with volatile and nonvolatile N-nitrosamines. Of a total of 145 samples analyzed 50 were found to contain N-nitrosodimethylamine (max. value found 24 micrograms/kg), 26 samples were contaminated with N-nitrosomorpholine (max. value found 640 micrograms/kg), and 25 samples contained N-nitrosodiethanolamine, a non-volatile carcinogen (max. value found 1400 micrograms/kg). These results are discussed and compared with other published data on NDE1A in cosmetics, with reference to potential human exposure and to possible preventive measures.
TL;DR: The presence and high activity of the GSH-dependent enzyme system in different segments of the human intestinal mucosa may reflect its role in the defense against toxic and putative carcinogenic xenobiotics entering the body via the gastrointestinal tract.
Abstract: A high content of total glutathione and high activities of both GSH S-aryltransferase (CDNB) and GSH peroxidase were found in different segments of the human intestinal mucosa comparable to findings in human gastric mucosa. Intraindividual comparisons of tumorous and nontumorous tissue specimens in patients with adenocarcinomas of the colon and rectum revealed no marked differences in their glutathione content and enzyme activities except in the sigma, where we found significantly lower GSH concentrations and higher GSH S-aryltransferase activities in the carcinomatous tissue. γ-Glutamyl-transpeptidase activity, a marker of neoplastic cell growth in experimental hepatocarcinogenesis, did not differ between tumorous and nontumorous tissue areas. The presence and high activity of the GSH-dependent enzyme system in different segments of the human intestinal mucosa may reflect its role in the defense against toxic and putative carcinogenic xenobiotics entering the body via the gastrointestinal tract.
TL;DR: This study does not support the suggestion that trichloroethylene itself is carcinogenic under realistic exposure conditions.
Abstract: Previous analytical studies of industrial samples of trichloroethylene (TRI) have revealed the presence of mutageneic and carcinogenic epoxides which, it was proposed, might be responsible for the carcinogenicity of such samples, as demonstrated with mice in other laboratories To test this hypothesis, Swiss mice (ICR/HA) of both sexes, bred and kept in SPF conditions, were dosed daily with TRI in corn oil by gavage (males: 24 g/kg, females: 18 g/kg) with or without the addition of epichlorohydrin (EPC, 08%, w/w), 1,2-epoxybutane (BO, 0,8%), or EPC+BO (025%+0,25%) for 18 months The ensuing observation period terminated at 106 weeks (from start of experiment) Gross and microscopic examination of all organs revealed a statistically significant increase in the incidence of forestomach papillomas and carcinomas after EPC-, BO-, and (EPC+BO)-stabilized samples of TRI, but not after pure, amine base-stabilized TRI This type of tumor is believed to be induced by the direct alkylating epoxides epichlorohydrin and epoxybutane, whose industrial use in stabilizing chlorinated aliphatic hydrocarbons should be discontinued No other significant increase in tumor incidences was found Again, this study does not support the suggestion that trichloroethylene itself is carcinogenic under realistic exposure conditions
TL;DR: Besides the morphological analysis, the determination of possible chemoresistance and chemosensitivity, as well as further investigations on fresh tumor tissue are included in the tissue examination.
Abstract: The diagnostic process in ovarian carcinoma is divided into the pre-and intraoperative procedures, examinations of tumor tissue, and follow-up. For preoperative diagnosis, the probability of a palpable adnexal mass being a malignant tumor should first be ascertained by sonography. This should be followed by an appropriate general examination, a search for tumor outside the abdominal cavity and in the liver parenchyma as well as by determination of markers. Intraoperative diagnosis determines the tumor stage and must be carried out all the more comprehensively when the ovarian carcinoma is more limited. Histologic subtype and degree of differentiation are in direct relation to the tumor stage, whereas the size of the primary tumor is often indirectly proportional to its extent. Besides the morphological analysis, the determination of possible chemoresistance and chemosensitivity, as well as further investigations on fresh tumor tissue are included in the tissue examination. Follow-up after a curative operation consists of gynecologic examination and Douglas lavages if tumor is still present in CT Scans and sonographs. To verify a relapse, laparoscopy can be used, but to ascertain a complete remission, a laparotomy is necessary.
TL;DR: In this paper, the quantity of N-nitrosoproline (NPRO) excreted in the urine after ingestion of proline and/or nitrate was estimated.
Abstract: To quantitate endogenous nitrosation reactions in man, the quantity of N-nitrosoproline (NPRO) excreted in the urine after ingestion of proline and/or nitrate was estimated. When this monitoring method (NPRO test) was applied in clinical and field studies, several hitherto unidentified N-nitroso compounds were frequently detected. These were recently identified as sulphur-containing N-nitrosamino acids, N-nitrosothiazolidine 4-carboxylic acid (NTCA), and trans- and cis-isomers of N-nitroso-2-methylthiazolidine 4-carboxylic acid (NMTCA).
TL;DR: It can be concluded that NK cells have a key role in the control of metastases of malignant disease, and that support of NK activity is very important for the prevention of metastase prevention.
Abstract: The mechanism of artificial and spontaneous metastases of tumor was analyzed in B16 melanoma cells and C57BL/6 mice by using anti-asialo GM1 antibody and anticancer agents. Single administrations of 500 μg anti-asialo GM1 antibody resulted in significantly decreased NK activity in spleen cells of C57BL/6 mice, lasting 10 days from the day following administration. Treatment with anti-asialo GM1 antibody never decreased the function of T lymphocytes measured by blastogenesis with phytohemagglutinin or T cell growth factor. The tumoricidal functions of activated macrophages but not of resident macrophages were decreased by in vivo treatment with anti-asialo GM1 antibody. The anti-asialo GM1 antibody was evaluated in terms of the enhancing effect on pulmonary metastases with regard to the timing of administration. Treatment with anti-asialo GM1 antibody 1 day before or on the day of tumor inoculation resulted in a substantial increase in the number of artificial pulmonary metastases. In the experimental system of spontaneous metastases, anti-asialo GM1 antibody most effectively increased the number of pulmonary metastases when administered 1–2 weeks before the removal of primary tumor, when the tumor cells are thought to be released into blood circulation from the primary site. In addition, accelerated growth of transplanted tumors at the primary site was observed in mice treated with anti-asialo GM1 antibody. These results strongly suggest that anti-asialo GM1 antibody enhances the incidence of in vivo tumor metastases and the growth of transplanted tumor mainly by suppressing the function of NK cells. The maximum effective dose (MED) of mitomycin C or its derivative (M-83) suppressed NK activity significantly, and pretreatment with these anticancer agents enhanced the growth of the artificial pulmonary and liver metastases. In contrast, the MED of cDDP showed no effect on the NK activity or the numbers of pulmonary and liver metastases. These results indicate that the depression of NK activity induced by chemotherapy results in the promotion of metastatic disease. From these studies it can be concluded that NK cells have a key role in the control of metastases of malignant disease, and that support of NK activity is very important for the prevention of metastases.
TL;DR: It was concluded that a tolerable therapeutic dose of indomethacin can reduce the carcinogenic activity of N-nitrosomethyl-urea in the large bowel.
Abstract: Nonsteroid antiinflammatory drugs such as indomethacin may play an important role in preventing the development of chemically induced experimental carcinomas of various organs including the large bowel in rats and mice. This effect might correlate with an inhibition of prostaglandin (PG) synthesis by these drugs. Sprague-Dawley rats were given three intrarectal doses of 4 mg N-nitrosomethyl-urea (MNU) within week 1 to induce large-bowel carcinomas. The experimental groups of rats received a 0.001% aqueous solution of indomethacin ad libitum as drinking water for days 1–8 and/or a subcutaneous injection of 500 μg/kg body weight of PGE2 immediately before and 2 h after each MNU dose. They were then maintained on basal diet and plain tap water without further treatment. At autopsy at week 31, the tumor incidence and the mean number of tumors per rat were 90% and 1.7 in untreated rats, 67% and 0.8 in indomethacin-treated rats, and 79% and 1.2 in indomethacin+PGE2-treated rats, respectively. The data indicate that indomethacin reduced the number of large-bowel tumors, while pharmacologic doses of PGE2 failed to reestablish the anticarcinogenic activity of indomethacin. It was concluded that a tolerable therapeutic dose of indomethacin can reduce the carcinogenic activity of MNU in the large bowel.
TL;DR: In vivo and in vitro data reported above give an unequivocal indication of the relative reactivity of the haloethanes examined with liver macromolecules from the two species and agree, on the whole, with the relative genotoxicity (DNA repair induction ability, mutagenicity and carcinogenicity) of the chemicals.
Abstract: The comparative interaction of equimolar amounts of 1,2-dichloroethane and 1,2-dibromoethane with rat and mouse nucleic acids was studied in both in vivo (liver, lung, kidney and stomach) and in vitro (liver microsomal and/or cytosolic fractions) systems. In vivo, liver and kidney DNA showed the highest labeling, whereas the binding to lung DNA was barely detectable. Dibromoethane was more highly reactive than dichloroethane in both species. With dichloroethane, mouse DNA labeling was higher than rat DNA labeling whatever the organ considered: the opposite was seen for the bioactivation of dibromoethane. RNA and protein labelings were higher than DNA labeling, with no particular pattern in terms of organ or species involvement. In vitro, in addition to a low chemical reactivity towards nucleic acids shown by haloethanes per se, both compounds were bioactivated by either liver microsomes and cytosolic fractions to reactive forms capable of binding to DNA and polynucleotides. UV irradiation did not photoactivate dibromoethane and dichloroethane. The in vitro interaction with DNA mediated by enzymatic fractions was PB-inducible (one order of magnitude, using rat microsomes). In vitro bioactivation of haloethanes was mainly performed by microsomes in the case of dichloroethane and by cytosolic fractions in the case of dibromoethane. When microsomes plus cytosol were used, rat enzymes were more efficient than mouse enzymes in inducing a dibromoethane-DNA interaction: the opposite situation occurred for dichloroethane-DNA interaction, and this is in agreement with the in vivo pattern. In the presence of both metabolic pathways, addition or synergism occurred. Dibromoethane was always more reactive than dichloroethane. An indication of the presence of a microsomal GSH transferase was achieved for the activation of dibromoethane. No preferential binding in vitro to a specific polynucleotide was found. Polynucleotide labeling was higher than (or equal to) DNA binding. The labeling of microsomal RNA and proteins and of cytosolic proteins was many times lower than that of DNA or polynucleotides. The in vivo and in vitro data reported above give an unequivocal indication of the relative reactivity of the haloethanes examined with liver macromolecules from the two species and agree, on the whole, with the relative genotoxicity (DNA repair induction ability, mutagenicity and carcinogenicity) of the chemicals.
TL;DR: Two dose schedules were used sequentially for cis-diamminedichloroplatinum II and among 13 patients evaluable for response, 2 partial responses were observed.
Abstract: Thirty-six (36) women with metastatic breast cancer refractory to conventional therapies were treated with cis-diamminedichloroplatinum II. Two dose schedules were used sequentially. The first 15 patients received platinum at a dose of 15 mg/m2 daily for 5 days at 28-day intervals. No response was noted in this group. Subsequently, 21 patients were treated with a dose of 100–120 mg/m2 at 28-day intervals, but with additional induced diuresis with saline, furosemide, and mannitol. Among 13 patients evaluable for response, 2 partial responses were observed.
TL;DR: UCLA-SO-M14, a human melanoma cell line, was cultured for ten passages in vitro and converted to an ascitic form, M14-A, by transplanting M14 into CD-1 nude mice and back into tissue culture, and the reproducibility of the formation of ascites and metastases was confirmed.
Abstract: UCLA-SO-M14, a human melanoma cell line, was cultured for ten passages in vitro. The line was converted to an ascitic form, M14-A, by transplanting M14 into CD-1 nude mice and back into tissue culture. The minimum number of M14-A cells that formed ascites in all mice (within 10–21 days) was 5×105, and over 80% of such mice developed macroscopic liver metastases. M14-A inoculated subcutaneously formed tumor at the site of injection, but rarely led to the development of metastases. However, when M14-A was inoculated subcutaneously in young mice (1–14 days old), more than 50% developed lung (but not liver) metastases. The reproducibility of the formation of ascites and metastases was confirmed by testing M14-A at various passages. M14-A may be useful as a model for the metastatic process in human melanoma.
TL;DR: Few generalizations can be made about these results, although it appeared that the 2-hydroxypropyl group was usually necessary for the induction of pancreas tumors in hamsters.
Abstract: The carcinogenic action of approximately 50 N-nitroso compounds, nitrosamines, and nitrosoalkylamides has been compared in rats and in Syrian golden hamsters. The compounds were administered PO, as far as possible at comparable dose rates. The relative potencies of the treatments were assessed mainly by the time to death of the animals with tumors. The esophagus and other parts of the upper gastrointestinal tract were the most common sites for tumor induction in rats, but the esophagus was hardly ever affected in hamsters, although several compounds induced tumors of the forestomach in both rats and hamsters. No conclusion could be drawn about the relative susceptibility of the rat and hamster to these N-nitroso compounds, which varied with different compounds. Few generalizations can be made about these results, although it appeared that the 2-hydroxypropyl group was usually necessary for the induction of pancreas tumors in hamsters.
TL;DR: N-Nitrosodiethanolamine, a potent carcinogen, has not so far been found to be mutagenic in a wide range of test systems, but when incubated with alcohol dehydrogenase (ADH) in the presence of NAD, NDELA is converted to a potent mutagen.
Abstract: N-Nitrosodiethanolamine (NDELA), a potent carcinogen, has not so far been found to be mutagenic in a wide range of test systems. In particular, mutagenicity testing in Salmonella typhimurium with rat liver S-9 mix or microsomal fraction used for activation has failed to indicate mutagenicity. However, when incubated with alcohol dehydrogenase (ADH) in the presence of NAD, NDELA is converted to a potent mutagen. A possible mechanism of activation comprises the generation of an aldehyde as a primary metabolite formed by NAD/ADH and its subsequent rearrangement into cyclic intermediates. The latter might either be further metabolized or spontaneously decompose into various alkylating agents and glycolaldehyde. Standard test conditions used for the Ames test will not favor the detection of mutagens to be activated by NAD/ADH because they require the presence of NADPH, whereas ADH needs NAD to become an activating enzyme, as shown for NDELA.
TL;DR: Moderate to good activity was found for all compounds as evidenced by a T/C value of 162 at a dose of 32mg/kg for (3b), 190 at a doses of 32 mg/ kg for (4a), and 139 at adose of 4 mg/kgfor (4b).
Abstract: There new diaziridine platinum(II) complexes(4a)-(4c), and a new azetidine platinum(II) complex (3b) were synthesized and tested against the lymphocytic leukemia P388 in mice.
Moderate to good activity was found for all compounds as evidenced by a T/C value of 162 at a dose of 32 mg/kg for (3b), 190 at a dose of 32 mg/kg for (4a), 139 at a dose of 4 mg/kg for (4b), and 142 at a dose of 20 mg/kg for (4c).
TL;DR: The highest dose induced urinary bladder cancer in all rats treated by week 91, decreasing yields being associated with lower dose levels, and the lowest dose (1 ppm) only induced two cases of papilloma.
Abstract: A dose-response study was carried out in male F344 rats with a specific urinary bladder carcinogen, N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN), which was administered as a solution in drinking water for up to 112 weeks BBN was given in four different concentrations, 50, 10, 5, and 1 ppm, to groups of 30 rats The highest dose induced urinary bladder cancer in all rats treated by week 91, decreasing yields being associated with lower dose levels: an incidence of 767% was observed with 10 ppm, followed by 200% with 5 ppm The lowest dose (1 ppm) only induced two cases of papilloma (69%)
TL;DR: Studies on the effect of high doses of AA and DHA added to the culture medium in single or fractionated doses revealed that fractionated administration is more efficient in inhibiting cell multiplication than single administration.
Abstract: The effects of AA and DHA on ATP C+ cell multiplication in vitro were studied by measuring incorporation of 3H thymidine into DNA. The results obtained demonstrate that both AA and DHA have the same effects: they favor cell multiplication at low doses and inhibit it at high doses. Experiments carried out with serial doses of both these substances revealed that AA is more efficient in determining both stimulating and inhibiting effects. The lesser efficiency of DHA may be attributed to its limited stability in culture medium. Studies on the effect of high doses of AA and DHA added to the culture medium in single or fractionated doses revealed that fractionated administration is more efficient in inhibiting cell multiplication than single administration.
TL;DR: In this paper, the irritant and tumor-promoting principles were isolated from the latex of E. resinifera Berg and from the resin derived from latex (euphorbium), which is commercially available as a drug.
Abstract: The irritant and tumor-promoting principles were isolated from the latex of Euphorbia resinifera Berg. and from the resin derived from latex (euphorbium), which is commercially available as a drug. The irritant Euphorbia factors RL 5 (mixture), RL 6, RL 7, RL 8, and RL 10 were identified as tigliane-type 12-deoxyphorbol esters each bearing, in the 13 position, either long-chain, partially methyl-substituted acyl residues (10-16 carbon atoms) or short-chain acyl residues (4 or 5 carbon atoms) or a (substituted) phenylacetyl group with a 20-acetoxy group. Euphorbia factors RL 15 (mixture), RL 16, RL 17, RL 18, and RL 21 are the corresponding 20-deacetylated derivatives thereof. The irritant Euphorbia factors RL 11, RL 12, RL 22, RL 23 were characterized as esters of the tigliane type 12-deoxy-16-hydroxyphorbol, i.e., 13-0-phenylacetyl-16-0-benzoyl-12-deoxy16-hydroxyphorbol-20- acetate (RL 11) and 13, 16-0-phenylacetyl, tigloyl-12-deoxy-16-hydroxy-phorbol-20-acetate (RL 12), RL 22 and RL 23 representing the respective 20-deacetylated derivatives. A mixture of irritant factors, RL 13, was shown to represent long-chain 3-esters of ingenane-type ingenol with similar acyl residues (10-16 carbon atoms, partially methyl-substituted) to RL 5 (RL 15) above. A further group of E. resinifera factors was of the daphnane type: RL 9 was identified as the extremely irritant 9,13,14-orthophenylacetate of resiniferonol-20-(4-hydroxy-3-methoxy)phenylacetate (Resiniferatoxin), RL 14 as the corresponding 9,13,14-orthophenylacetate of resiniferonol, and RL 20 as 14-0-phenylacetylresiniferonol-20-(4-hydroxy-3-methoxy)-phenylacet ate (Proresiniferatoxin). The irritant factors specified below were accompanied by nonirritant esters of the tigliane type 12,20-dideoxyphorbol, i.e., RL 1 and RL 2, and of the lathyrane type ingol, i.e., RL 3 and RL 4. In tumor promotion experiments the mixture of homologous irritant factors RL 13 was equipotent with the standard tumor promoter TPA, but at 10 times the dose of TPA. Several others of the irritant factors had low activity as tumor promotors, but of the few tumors obtained in these experiments a high percentage was malignant. The very high irritant activity of the latex may be ascribed to resiniferatoxin (RL 9), representing a new class of rapidly acting skin irritants. No promoting activity was detected on administration of the highly irritant resiniferatoxin.
TL;DR: The differences in activity of the diastereomers (±)-2d and meso-2d, for which distinct influences on the DNA secondary structure can be demonstrated CD spectroscopically may be explained by a steric hindrance of the drug-DNA interaction.
Abstract: Ring unsubstituted dichloro(diphenylethylenediamine)platinum(II) complexes show a dependence of their antitumor activity on the configuration and position of phenyl rings in ethylenediamine ligand. Dichloro(1,1-diphenylethylenediamine)platinum(II) (1d) and meso-dichloro(1,2-diphenylethylenediamine)-platinum(II) (meso-2d) have a weaker effect on the human breast-cancer cell line MDA-MB 231 and on rat leukemia L5222 than (±)-dichloro(1,2-diphenylethylenediamine)platinum(II) ((+)-2d) and its enantiomers (+)-2d and (-)-2d which cause marked and comparable inhibition of both tumors; (±)-2d is also active on ADJ/PC 6 plasmacytoma of the mouse and on cisplatin-, daunomycin-, and cisplatin/daunomycin-resistant Ehrlich ascites tumors of the mouse. The differences in activity of the diastereomers (±)-2d and meso-2d, for which distinct influences on the DNA secondary structure can be demonstrated CD spectroscopically may be explained by a steric hindrance of the drug-DNA interaction.
TL;DR: Following a single dose of (14C-methyl)procarbazine to newborn animals, methylpurine values were 30–60 times lower than after prenatal administration, which suggests that DNA alkylation in nonhepatic tissues occurs by systemic distribution of a proximate carcinogen formed in the adult rat liver.
Abstract: The cytostatic drug procarbazine has previously been shown to be a potent transplacental neurotropic carcinogen in rats. Following a single IP administration of (14C-methylprocarbazine (110 mg/kg) on day 22 of gestation, methylation products with cellular DNA were determined in fetal and maternal rat organs. The concentration of the major adduct N7-methylguanine was highest in the maternal liver (224 μmol/mol guanine). Fetal and nonhepatic maternal tissues exhibited significantly lower levels, but differed little from each other. In brain, lung, intestines, and placenta the O
6-methylguanine/N7-methylguanine ratio was close to 0.11, indicating that procarbazine, like other methylating carcinogens, initiates malignant transformation via methyldiazonium hydroxide as the ultimate reactant. Following a single dose of (14C-methyl)procarbazine to newborn animals, methylpurine values were 30–60 times lower than after prenatal administration. This suggests that DNA alkylation in nonhepatic tissues occurs by systemic distribution of a proximate carcinogen formed in the adult rat liver.