Interspecific and Spatial Comparisons of Perfluorinated Compounds in Bighead and Silver Carp in the Illinois River, Illinois, USA.

We examined perfluoroalkyl compounds (PFC) in bighead (BHCP; Hypophthalmichthys nobilis) and silver (SVCP; H. molitrix) carp from the Illinois River, Illinois, USA. Summed PFC concentrations in whole fish did not differ by species or river reach. Perfluorooctanesulfonate (PFOS) concentrations were much greater in whole fish (16.4 ng/g) than in fillets (3.4 ng/g). PFOS concentrations represented 35%-51% of total measured PFC concentrations in whole fish, and in fillets were weakly associated with carcass mass (R2=0.17, p=0.01) and % carcass lipid (R2=0.16, p=0.01). No such relationship was observed in whole fish. The relationship between concentrations of individual PFC congeners in whole fish and carcass mass or % lipid content varied by species. Our study demonstrated that filter-feeders such as BHCP and SVCP can accumulate measureable concentrations of PFC and these results are important for understanding the fate of these compounds in large river systems.

The multiple functions of heme oxygenase-1 in the liver.

Heme oxygenases (HO) are essential enzymes which degrade heme into carbon monoxide (CO), biliverdin and free iron. Due to its anti-inflammatory, anti-apoptotic and, as recently described, anti-viral properties the inducible HO isoform HO-1 is an important molecule which could find its way into therapy of gastrointestinal diseases. Acute and chronic liver injuries including acute liver failure, alcoholic or viral hepatitis, chronic inflammation, fibrosis, cirrhosis, and hepatocellular carcinoma are life threatening diseases and as a consequence might result in the necessity of liver transplantation. HO-1 as well as its reaction products of heme degradation has been linked to cytoprotection. HO-1 induction in rodent models of acute and chronic hepatic inflammation resulted in improvement of liver damage and down-regulation of pro-inflammatory cytokine levels. Furthermore HO-1 induction interfered with fibrosis progression in mice and partially resolved existing fibrosis. Likewise, HO-1 induction interfered with replication of hepatitis viruses B and C, which frequently are the reason for chronic hepatitis and subsequent tumor growth. Liver transplantation is limited by ischemia/reperfusion (I/R) injury, which is characterized by hypoxia and nutrient deficiency resulting in oxidative stress, apoptosis and immune activation. Induction of HO-1 and application predominantly of CO have been shown to interfere with I/R liver injury and to improve recipient and graft survival. On the other hand HO-1 has been shown to be over-expressed in various tumors, including hepatocellular carcinoma (HCC). Due to its anti-apoptotic properties this bears the risk to promote tumor growth. Anti-apoptotic effects are predominantly mediated by CO. This review aims to summarize beneficial as well as detrimental effects of HO-1 and its products within the liver.

A novel technique for selective NF-kappaB inhibition in Kupffer cells: contrary effects in fulminant hepatitis and ischaemia-reperfusion.

BACKGROUND AND AIMS: The transcription factor nuclear factor kappa B (NF-kappaB) has risen as a promising target for anti-inflammatory therapeutics. In the liver, however, NF-kappaB inhibition mediates both damaging and protective effects. The outcome is deemed to depend on the liver cell type addressed. Recent gene knock-out studies focused on the role of NF-kappaB in hepatocytes, whereas the role of NF-kappaB in Kupffer cells has not yet been investigated in vivo. Here we present a novel approach, which may be suitable for clinical application, to selectively target NF-kappaB in Kupffer cells and analyse the effects in experimental models of liver injury. METHODS: NF-kappaB inhibiting decoy oligodeoxynucleotides were loaded upon gelatin nanoparticles (D-NPs) and their in vivo distribution was determined by confocal microscopy. Liver damage, NF-kappaB activity, cytokine levels and apoptotic protein expression were evaluated after lipopolysaccharide (LPS), d-galactosamine (GalN)/LPS, or concanavalin A (ConA) challenge and partial warm ischaemia and subsequent reperfusion, respectively. RESULTS: D-NPs were selectively taken up by Kupffer cells and inhibited NF-kappaB activation. Inhibition of NF-kappaB in Kupffer cells improved survival and reduced liver injury after GalN/LPS as well as after ConA challenge. While anti-apoptotic protein expression in liver tissue was not reduced, pro-apoptotic players such as cJun N-terminal kinase (JNK) were inhibited. In contrast, selective inhibition of NF-kappaB augmented reperfusion injury. CONCLUSIONS: NF-kappaB inhibiting decoy oligodeoxynucleotide-loaded gelatin nanoparticles is a novel tool to selectively inhibit NF-kappaB activation in Kupffer cells in vivo. Thus, liver injury can be reduced in experimental fulminant hepatitis, but increased at ischaemia-reperfusion.

Targeted drug delivery by in vivo coupling to endogenous albumin: an albumin-binding prodrug of methotrexate (MTX) is better than MTX in the treatment of murine collagen-induced arthritis.

OBJECTIVE: To examine the effect of an albumin-binding prodrug of methotrexate (MTX) in the treatment of murine collagen-induced arthritis (CIA). METHODS: The prodrug AWO54 with the formula EMC-d-Ala-Phe-Lys-Lys-MTX binds selectively to the cysteine-34 position of endogenous albumin, which acts as a macromolecular drug carrier for MTX to the site of inflammation. The CIA model was used to evaluate the anti-arthritic effect of the compound after intravenous application. RESULTS: The albumin-bound form of AWO54 was efficiently cleaved by cathepsin B and plasmin, two proteases that are overexpressed in rheumatoid arthritis, and release a MTX lysine derivative. AWO54 suppressed CIA in a dose-dependent manner and was significantly better than MTX. To obtain a similar effect only about 20% of the MTX-equivalent dose of AWO54 had to be given. The efficacy of the drug was tested in two different stages of CIA: while both, MTX and AWO54 inhibited arthritis in an early stage of the disease, in a later stage only AWO54 showed a significant inhibitory effect in comparison with control. CONCLUSION: Targeted drug delivery by in vivo coupling of a prodrug of MTX to endogenous albumin is better than MTX in the treatment of CIA.

Inducible nitric oxide synthase is critical for immune-mediated liver injury in mice.

Concanavalin A (Con A) causes severe TNF-alpha-mediated and IFN-gamma-mediated liver injury in mice. In addition to their other functions, TNF-alpha and IFN-gamma both induce the inducible nitric oxide (NO) synthase (iNOS). Using different models of liver injury, NO was found to either mediate or prevent liver damage. To further elucidate the relevance of NO for liver damage we investigated the role of iNOS-derived NO in the Con A model. We report that iNOS mRNA was induced in livers of Con A-treated mice within 2 hours, with iNOS protein becoming detectable in hepatocytes as well as in Kupffer cells within 4 hours. iNOS-/- mice were protected from liver damage after Con A treatment, as well as in another TNF-alpha-mediated model that is inducible by LPS in D-galactosamine-sensitized (GalN-sensitized) mice. iNOS-deficient mice were not protected after direct administration of recombinant TNF-alpha to GalN-treated mice. Accordingly, pretreatment of wild-type mice with a potent and specific inhibitor of iNOS significantly reduced transaminase release after Con A or GalN/LPS, but not after GalN/TNF-alpha treatment. Furthermore, the amount of plasma TNF-alpha and of intrahepatic TNF-alpha mRNA and protein was significantly reduced in iNOS-/- mice. Our results demonstrate that iNOS-derived NO regulates proinflammatory genes in vivo, thereby contributing to inflammatory liver injury in mice by stimulation of TNF-alpha production.

Phase I trial of weekly scheduling and pharmacokinetics of titanocene dichloride in patients with advanced cancer.

PURPOSE: To determine the maximum-tolerated dose (MTD) and the dose-limiting toxicities (DLTs) of a weekly schedule of titanocene dichloride (TD) and to define the pharmacokinetics of titanium in plasma and urine. PATIENTS AND METHODS: Twenty patients with a median age of 58 years received 83 courses of TD. TD was given as 1-hour infusion at escalating doses from 70 to 185 mg/m2/wk. Pharmacokinetic analysis was performed in eight patients for total plasma titanium (TPTi) and in three patients for ultrafiltrable titanium (UFTi). RESULTS: At the fifth dose level (185 mg/m2/wk), a variety of DLTs were seen in five patients: fatigue in three, bilirubinemia in one, and hypokalemia in two. A further six patients were treated at 140 mg/m2; only one had dose-limiting creatinine elevation and this dose was therefore defined as the MTD. No myelosuppression or alopecia were observed. One patient with adenocarcinoma of unknown primary had a minor response. Pharmacokinetic analysis showed that TPTi maximum concentration (Cmax) values were linear with dose and elimination of TPTi was triphasic with a long terminal half-life (t1/2; median, 165 hours; range, 89 to 592). Between 7% and 24.3% of the total of administered titanium was eliminated in urine over the first 24 hours. In contrast, UFTi elimination was described by a one-compartment model with a t1/2 of 0.41 hours; peak levels of UFTi were 5.2% +/- 2.5% those of TPTi. CONCLUSION: The MTD of TD given on a weekly schedule is 140 mg/m2, with cumulative, but reversible creatinine and bilirubin elevation being the DLTs.

Pairing-dependent mislocalization of a Drosophila brown gene reporter to a heterochromatic environment.

We describe the precise positioning of a reporter gene within heterochromatin where it may be silenced. A transposition of the 59E-60A region into pericentric heterochromatin ensnares distal 59E-60A via somatic pairing. The frequency with which a brown (bw) reporter gene in 59E is silenced is influenced by chromosomal configurations. Silencing occurs only when the bw+ reporter is unpaired due to heterozygosity with a deficiency, where the frequency of bw+ reporter expression is correlated with the extent of bw gene and flanking sequence present. Surprisingly, the frequency of pairing between the transposition in heterochromatin and distal 59E observed cytologically is indistinguishable from the frequency of pairing of homologous chromosomes at 59E in wild-type larval brains, regardless of configuration. Therefore, bringing a susceptible reporter gene into close proximity with heterochromatin does not necessarily affect its expression, but local pairing changes resulting from altered chromosomal configurations can lead to silencing. We also find that an ensnared distal copy of bw that is interrupted by a heterochromatic insertion enhances silencing. This demonstrates that bw can be simultaneously acted upon by pericentric and distal blocks of heterochromatin.

Comparative analysis of position-effect variegation mutations in Drosophila melanogaster delineates the targets of modifiers.

In Drosophila melanogaster, heterochromatin-induced silencing or position-effect variegation (PEV) of a reporter gene has provided insights into the properties of heterochromatin. Class I modifiers suppress PEV, and class II modifiers enhance PEV when the modifier gene is present in fewer than two doses. We have examined the effects of both class I and class II modifiers on four PEV mutations. These mutations include the inversions In(1)w(m4) and In(2R)bw(VDe2), which are classical chromosomal rearrangements that typify PEV mutations. The other mutations are a derivative of brown(Dominant), in which brown+ reporters are inactivated by a large block of heterochromatin, and a P[white+] transposon insertion associated with second chromosome heterochromatin. In general, we find that class I modifiers affect both classical and nonclassical PEV mutations, whereas class II modifiers affect only classical PEV mutations. We suggest that class II modifiers affect chromatin architecture in the vicinity of reporter genes, and only class I modifiers identify proteins that are potentially involved in heterochromatin formation or maintenance. In addition, our observations support a model in which there are different constraints on the process of heterochromatin-induced silencing in classical vs. nonclassical PEV mutations.

Structure and expression of hybrid dysgenesis-induced alleles of the ovarian tumor (otu) gene in Drosophila melanogaster.

Mutations at the ovarian tumor (otu) gene of Drosophila melanogaster cause female sterility and generate a range of ovarian phenotypes. Quiescent (QUI) mutants exhibit reduced germ cell proliferation; in oncogenic (ONC) mutants germ cells undergo uncontrolled proliferation generating excessive numbers of undifferentiated cells; the egg chambers of differentiated (DIF) mutants differentiate to variable degrees but fail to complete oogenesis. We have examined mutations caused by insertion and deletion of P elements at the otu gene. The P element insertion sites are upstream of the major otu transcription start sites. In deletion derivatives, the P element, regulatory regions and/or protein coding sequences have been removed. In both insertion and deletion mutants, the level of otu expression correlates directly with the severity of the phenotype: the absence of otu function produces the most severe QUI phenotype while the ONC mutants express lower levels of otu than those which are DIF. The results of this study demonstrate that the diverse mutant phenotypes of otu are the consequence of different levels of otu function.

Phase I clinical and pharmacokinetic study of titanocene dichloride in adults with advanced solid tumors.

This Phase I dose-escalation clinical trial of a lyophilized formulation of titanocene dichloride (MKT4) was conducted to determine the maximum tolerated dose, the dose-limiting toxicity (DLT), and pharmacokinetics of titanium (Ti) after a single i.v. infusion of MKT4. Forty patients with refractory solid malignancies were treated with a total of 78 courses. Using a modified Fibonacci scheme, 15 mg/m2 initial doses of titanocene dichloride were increased in cohorts of three patients up to level 11 (560 mg/m2) if DLT was not observed. The maximum tolerated dose was 315 mg/m2, and nephrotoxicity was DLT. Two minor responses (bladder carcinoma and non-small cell lung cancer) were observed. The pharmacokinetics of plasma Ti were assessed in 14 treatment courses by atomic absorption spectroscopy. The ratio for the area under the curve(0-infinity) in plasma and whole blood was 1.2. The following pharmacokinetic parameters were determined for plasma, as calculated in a two-compartment model: biological half-life t1/2beta in plasma was 22.8+/-11.2 h (xh +/- pseudo-SD), peak plasma concentration cmax approximately 30 microg/ml at a dose of 420 mg/m2, distribution volume Vss= 5.34+/-2.1 L (xa +/- SD), and a total clearance CItotal = 2.58+/-1.23 ml/min (xa +/- SD). There was a linear correlation between the area under the curve(0-infinity) of Ti in plasma and the titanocene dichloride dose administered with a correlation coefficient r2 of 0.8856. Plasma protein binding of Ti was in the 70-80% range. Between 3% and 16% of the total amount of Ti administered were renally excreted during the first 36 h. The recommended dose for Phase II evaluation is 240 mg/m2 given every 3 weeks with i.v. hydration to reduce renal toxicity.

Titanocendichloride activity in cisplatin and doxorubicin-resistant human ovarian carcinoma cell lines.

The activity of a new organometallic compound, titanocendichloride, was evaluated in doxorubicin- and cisplatin-resistant human ovarian carcinoma cell lines in vitro. Titanocendichloride showed no cross resistance to doxorubicin in two multidrug resistant sublines of A2780. Furthermore, the cell line A2780 CP3, which is about 20-fold resistant to cisplatin was only 2.5-fold resistant to titanocendichloride, indicating a lack of cross resistance between the two metal compounds. These results were confirmed in vivo where titanocendichloride showed a much stronger inhibitory effect in cisplatin-resistant human ovarian carcinoma xenografts than cisplatin.

Functional and structural defects in HIV type 1 nef genes derived from pediatric long-term survivors.

DNA sequences and three distinct in vitro functions of Nef were evaluated in a group of seven perinatally infected children. nef gene sequences obtained before and after virus culture showed that one of the five non-/slow progressors harbored a virus with large deletions. nef genes from the remaining four children were full length but contained discrete changes at a higher frequency than the rapid progressors. In functional studies, 40 of 44 Nef proteins derived from the whole study group were capable of binding the cellular serine kinase p62, indicating that this function is well conserved among naturally occurring viruses. In contrast, representative Nef proteins derived from the long-term non-/slow progressors were found to be defective or far less capable of enhancing viral replication and/or viral infectivity in herpesvirus saimiri-transformed human T cells and peripheral blood mononuclear cells. On reversion of highly prevalent point mutations in the defective proteins, viral replication could be restored to wild-type levels. Our results suggest that nef genes derived from pediatric long-term nonprogressors have gross deletions in isolated cases but a higher prevalence of discrete changes that may impair Nef function in primary T cell assays, but not all functions reported for Nef.

Phase-I tolerability study of 5-methyltetrahydrofolate in combination with a 4-hour infusion of 5-Fluorouracil in cancer-patients.

5-methyltetrahydrofolate (MTHF) is a main serum metabolite of 5-formyltetrahydrofolate (folinic acid, FA), a standard agent for potentiation of the cytotoxic activity of 5-fluorouracil (5-FU). The clinical application of MTHF instead of FA as a precursor of the biologically active metabolite 5,10-methyltetrahydrofolate (mTHF) is based on favorable pharmacologic characteristics of MTHF described so far. In this phase I study 18 patients with advanced solid malignancies were treated with MTHF for 5 days at doses ranging from 100 to 500 mg/m(2)/day in combination with a fixed dose of 500 mg/m2/day 5-FU given as a 4-hour infusion. The treatment was repeated after 21 days. The toxicity observed was mainly gastrointestinal with loss of appetite, nausea and vomiting (up to WHO grade III), and less frequently stomatitis, decline of hemoglobin and hematuria (up to WHO grade II). The frequency and severity of side effects seen were not related to the dose of MTHF. Cumulative toxicity was not observed. The MTD was not reached up to an MTHF dose of 500 mg/m(2)/day. Objective remissions were not seen. The study was terminated on the basis of results showing comparable 5,10-methylenetetrahydrofolate (mTHF) tumor- and tissue levels after administration of MTHF or FA.

Antitumor activity of treosulfan against human breast carcinomas.

Treosulfan (L-threitol-1,4-bismethanesulfonate, Ovastat) is a bifunctional alkylating agent that shows a formal structural similarity to busulfan and is applied clinically to patients suffering from ovarian cancer. The present study demonstrated the pronounced antitumor activity of this drug against three of five human breast carcinomas xenografted to athymic mice. It was shown that treosulfan is capable of inducing irreversible and complete remission of the heterotransplanted human breast carcinomas MDA-MB-436 and MX-1 within 14 days after drug application and of effecting growth inhibition by more than 90% in the MDA-MB-435S xenograft. In all three carcinomas, treosulfan caused more pronounced growth reduction than did equitoxic doses of the alkylator cyclophosphamide. Adriamycin, an intercalating cytostatic agent that is an important component of clinical nonhormonal chemotherapy of breast carcinomas, induced only partial remission of these three xenografts and inhibited the tumor growth by 80%-90% (MDA-MB-436, MX-1) and by 70%-80% (MDA-MB-435S), respectively. In the M 3 xenograft, treosulfan just led to a retardation and stagnation of tumor growth; it was again more effective than Adriamycin but was clearly less active than cyclophosphamide. The FM 2 breast carcinoma, finally, was the only xenograft whose growth was not influenced by treosulfan at doses up to that which was lethal to 50% of the treated mice (LD50 value). These results confirm that treosulfan is effective against human breast carcinomas. Because of this activity as well as the known low toxicity and good clinical compatibility of treosulfan, it should be considered for introduction into nonendocrine chemotherapeutic regimens against human breast carcinomas and investigation in clinical trials.

Antitumor activity of treosulfan in human lung carcinomas.

Treosulfan (L-threitol 1,4-bismethanesulfonate, Ovastat) is an alkylating agent and a structural analogue of busulfan. It has been established in the clinical chemotherapy of human ovarian carcinomas for several years and has additionally been shown to be effective against xenografted human breast carcinomas. No other human carcinoma is yet known to be sensitive to treosulfan. The present study confirms the pronounced and significant antitumor activity of treosulfan against heterotransplanted human lung carcinomas of both the small-cell and the non-small-cell type. Treosulfan reduced the growth of all four small-cell lung carcinomas that were investigated in a significant manner. It was even more active than equitoxic doses of the clinically approved cytostatics ifosfamide, cisplatin, and etoposide toward three of them and induced long-lasting growth reductions (60-98% of control tumor size) corresponding to partial and nearly complete remissions. In the case of the nine non-small-cell lung carcinomas investigated, treosulfan effected significant growth inhibition of more than 50%, again in all of them, and was more active than the comparative compounds ifosfamide, mitomycin C, and cisplatin at least in one of four epidermoid lung carcinomas, one large-cell carcinoma, and one of three lung adenocarcinomas. These results are remarkable and unexpected, and the present study should be followed rapidly by phase II clinical trials of treosulfan against human lung carcinomas of both the small-cell and the non-small-cell type.

Antitumor activity of new organometallic compounds in human ovarian cancer cell lines and comparison to platin derivatives.

Cisplatin, Carboplatin and new compounds such as Paclitaxel and Docetaxel are effective drugs in the treatment of ovarian cancer. Multidrug resistance however remains an issue in ovarian cancer. The search for new effective drugs will remain of the highest priority in the field of cancer research. The in vitro and in vivo growth inhibiting potencies of two new metallocene dichlorides, Titanocendichloride and Vanadocendichloride, were compared to Cisplatin and Carboplatin using 20 permanent human ovarian cancer cell lines. Under in vivo and in vitro conditions Cisplatin was more effective than Carboplatin. Under in vitro conditions a Vanadocendichloride concentration of as low as 1.5 x 10(-7) mol/l resulted in a 50% decrease in the cell proliferation. Titanocendichloride inhibited cellular growth only at concentrations of 10(-4) mol/l. In contrast, Titanocendichloride was more effective in inhibiting growth of xenotransplanted ovarian cancer cell lines in nude mice. The clinically supposed equipotentiality of Carboplatin should be handled cautiously. The new organometallic substances clearly exhibit antiproliferative properties in ovarian cancer cells and are considered for clinical phase I trials.

Treosulfan in the treatment of advanced ovarian cancer: a randomised co-operative multicentre phase III-study.

BACKGROUND: In August 1988 a randomised phase III multicenter trial was started in order to compare cisplatinum/treosulfan (PT) with standard cisplatinum/cyclophosphamide (PC) in advanced ovarian carcinoma, aiming at lower toxicity and maintained efficiency. PATIENTS AND METHODS: Five hundred and nineteen patients were enrolled into the protocol. Final evaluation after a median observation time of more than five years was made in July 1996 and included 398 eligible patients, of whom 366 were evaluable regarding efficiency and 290 in respect of toxicity. The tumour stages were classified as FIGO II in 53, FIGO III in 244 and FIGO IV in 68 patients. The patients were stratified regarding post-operative tumour burden. RESULTS: Hematological and gastrointestinal toxicity WHO > = 3 were comparable between the two study arms though a significant difference could be demonstrated regarding alopecia (PT 8% vs. PC 47% after six cycles). The median time to progression as the main efficiency item was in favour of the study schedule (PT 20.6 vs. PC 15.1 months) while significant differences were neither observed in the whole study group nor in the analysed subgroups (R0, < 2 cm, > = 2 cm). The same held true for overall survival. CONCLUSION: PT may be recommended as a less toxic substitute for the former standard PC. After the acceptance of paclitaxel/cisplatin as a new standard, the role of treosulfan should be investigated regarding adjuvant therapy in patients without residual tumor, as a potential partner in triple or sequential treatment and in second-line treatment.

In vitro activity of titanocenedichloride in human renal cell carcinoma compared to conventional antineoplastic agents.

In the present study, the in vitro activity of titanocenedichloride, a novel anticancer metal complex, in eleven primary renal cell carcinoma (RCC) specimens was evaluated by an adenosine triphosphate (ATP) bioluminescence assay. Compared to standard antineoplastic agents such as cisplatin, doxorubicin, mitoxantrone and vinblastine, titanocenedichloride was found to exhibit higher cytotoxicity. Four tumors showed strong sensitivity to the new agent. Three of them were resistant to conventional cytostatics. These findings indicated a lack of cross-resistance between titanocenedichloride and both natural compounds as well as platin analogues. Since mitoxantrone was also found to exhibit marked antineoplastic activity with no evidence of cross-resistance to titanocenedichloride, the combination of both drugs in RCC should be evaluated further with additional in vitro studies.

In vitro activity of titanocenedichloride versus cisplatin and doxorubicin in primary and recurrent epithelial ovarian cancer.

BACKGROUND: Titanocenedichloride (MKT 4) is a new antineoplastic metal complex with proven activity in several experimental tumors. MATERIAL AND METHODS: In the present study, the cytotoxic activity of titanocenedichloride in fourteen primary and twelve recurrent ovarian carcinomas (OvCA) was evaluated by an in vitro adenosine triphosphate (ATP) bioluminescence assay. RESULTS: In primary tumors, MKT 4 was found to be at least as effective as cisplatin (DDP) and doxorubicin (DOX). In samples derived from pretreated patients, titanocenedichloride was even more active. In both groups of tumors, a lack of cross resistance between the two metal compounds as well as between MKT 4 and DOX was apparent. The new agent was found to be active in eight of seventeen DDP-resistant (primaries: n = 4; recurrences n = 4) and also eight of seventeen DOX-resistant tumors (primaries: n = 4; recurrences n = 4). CONCLUSIONS: These results indicate a remarkable in vitro activity of titanocenedichloride in native OvCA specimens, even in those exhibiting resistance against cisplatin or doxorubicin. The putative role of this novel drug for the future therapy of OvCA should be evaluated by additional in vitro and in vivo studies.

[Association of chronic myelosis and cancer]. / Zusammentreffen von chronischer Myelose und Krebs

During the period between 1948-1963 a total of 3,200 tumor patients were treated in the First and Second Medical Clinics of Tg.-Mures. In these tumor patients as well as the skin cancer patients who were treated with radiotherapy the authors found in 1.5% of the patients a leukocytosis of more than 20,000. In the last ten years (1964-1974), however, in the Second Medical Clinic only, 5% of 516 tumor patients showed a leukocytosis exceeding 20,000. In the first group of patients (3,200 cases) 0.03% showed more than 50,000 leukocytes, in the other group of 516 patients 0.2% showed more than 50,000 leukocytes. These values point towards a leukemoid reaction. A shift to the left to the myelocytes or beyond in the blood picture was found in the Second Medical Clinic in 10% of patients with carcinoma during the year of 1974. In 6% of the cases erythroblasts in the peripheral blood were seen, too. This deviation occurred often independent of the total number of leukocytes and was of a temporary nature. During the same time (1949-1974) 128 patients with chronic myeloid leukemia were treated in both departments as in-patients. 6 cases (i.e., 4.6%) had a chronic myelosis simultaneous with carcinoma, in one case together with an osteosarcoma. The diagnosis was confirmed in all cases by autopsy.