Biomedical subjects

J Hofmann

Publications and source records attributed to J Hofmann.

At least 19 recordsLinked to original sources

PubMed2000

Antiapoptotic activity of Stat5 required during terminal stages of myeloid differentiation.

Stat5 is activated by multiple receptors of hematopoietic cytokines. To study its role during hematopoiesis, we have generated primary chicken myeloblasts expressing different dominant-negative (dn) alleles of Stat5. This caused a striking inability to generate mature cells, due to massive apoptosis during differentiation. Bcl-2 was able to rescue differentiating cells expressing dnStat5 from apoptosis, suggesting that during cytokine-dependent differentiation the main function of the protein is to ensure cell survival. Our findings with dnStat5-expressing chicken myeloblasts were confirmed with primary hematopoietic cells from Stat5a/Stat5b-deficient mice. Bone marrow cells from these animals displayed a strong increase in apoptotic cell death during GM-CSF-dependent functional maturation in vitro. The antiapoptotic protein Bcl-x was induced by GM-CSF and IL-3 in a Stat5-dependent fashion. Ectopic expression of Bcl-x rescued Stat5-deficient bone marrow cells from apoptosis, indicating that Stat5 promotes the survival of myeloid progenitor cells through its ability to induce transcription of the bcl-x gene. Finally, the recruitment of myeloid cells to inflammatory sites was found strongly impeded in Stat5-deficient mice. Taken together, our findings suggest that Stat5 may promote cytokine-dependent survival and proliferation of differentiating myeloid progenitor cells in stress or pathological situations, such as inflammation.

Alleles↗

PubMed2000

Persistent fetal rubella vaccine virus infection following inadvertent vaccination during early pregnancy.

Inadvertent immunisation of seronegative women with RA27/3 rubella virus live-attenuated vaccine several weeks before and after conception is described. Whereas in 5 cases the vaccine virus was not transmitted vertically, in 1 case vaccination led to the development of persistent fetal infection with prolonged virus shedding for more than 8 months. Sequence analysis carried out on isolates from amniotic fluid, from cord blood leukocytes as well as from infantile urine confirmed an infection by the vaccine strain. At birth, the newborn infant exhibited none of the symptoms compatible with the congenital rubella syndrome and signs indicative for development of late onset disease are not apparent. This observation constitutes the first unequivocal documented case of rubella vaccine virus related to persistent fetal infection.

Adult↗

PubMed2000

High incidence of parvovirus B19 DNA in synovial tissue of patients with undifferentiated mono- and oligoarthritis.

A common problem in rheumatological practice is inflammatory joint disease that cannot be classified. The prognosis of such undifferentiated arthritides is uncertain. The synovial tissue of 41 consecutive patients with various forms of arthritis was tested for the presence of viral DNA in a diagnosis-unaware fashion, using the polymerase chain reaction (PCR). Of all tested viruses, cytomegalovirus and parvovirus B19 were positive (each in 10 patients, two double-positives), whereas herpes simplex virus was positive in two patients. Rubella virus RNA was detected in three specimens. When the positivity for viral material was analysed in terms of distribution among the various diagnostic groups, it became evident that five out of 10 parvovirus B 19-positive patients belonged to the undifferentiated arthritis group, whereas cytomegalovirus-positive patients were spread among all diagnostic groups. This indicates the possibility of a new diagnostic category of undifferentiated mono- and oligoarthritis, which can be identified by the presence of parvovirus B19 DNA in synovial tissue.

Adolescent↗

PubMed2000

Rubella virus nonstructural protein 2 is a minor immunogen.

The full-length nonstructural protein P90 of rubella virus (RV) was expressed as recombinant protein in Escherichia coli bacteria, as well as in Vero cells. Monoclonal antibodies raised against the protein specifically reacted with the protein in both P90-transfected and RV infected Vero cells. Ninety human sera obtained from reconvalescents, vaccinees and patients with acute RV infection were tested for reactivity against the P90 protein. A weak immune reaction was detected only in a small minority (8%), indicating that P90 is minor immunogen for RV and is not suitable for diagnostic purposes.

Animals↗

PubMed2000

Impact of penicillin susceptibility on medical outcomes for adult patients with bacteremic pneumococcal pneumonia.

The impact of penicillin susceptibility on medical outcomes for adult patients with bacteremic pneumococcal pneumonia was evaluated in a retrospective cohort study conducted during population-based surveillance for invasive pneumococcal disease in the greater Atlanta region during 1994. Of the 192 study patients, 44 (23%) were infected with pneumococcal strains that demonstrated some degree of penicillin nonsusceptibility. Compared with patients infected with penicillin-susceptible pneumococcal strains, patients whose isolates were nonsusceptible had a significantly greater risk of in-hospital death due to pneumonia (relative risk [RR], 2.1; 95% confidence interval [CI], 1-4.3) and suppurative complications of infection (RR, 4.5; 95% CI, 1-19.3), although only risk of suppurative complications remained statistically significant after adjustment for baseline differences in severity of illness. Among adults with bacteremic pneumococcal pneumonia, infection with penicillin-nonsusceptible pneumococci is associated with an increased risk of adverse outcome.

Adult↗

PubMed2000

Serum protein 90K/Mac-2BP is an independent predictor of disease severity during hepatitis C virus infection.

The serum protein designated 90K/Mac-2BP has been found at elevated concentrations in the sera of patients with various types of cancer and viral infections. The importance of the 90K/Mac-2BP serum concentrations in predicting the response towards interferon-alpha treatment for hepatitis C virus (HCV) infection prompted us to utilize a new ELISA for soluble human 90K/Mac-2BP to monitor the serum concentrations of this protein in our HCV-positive patients. Seventy HCV-PCR and anti-HCV antibody positive patients were analyzed for their serum levels of aspartate aminotransferase, alanine aminotransferase, gamma-glutamyltransferase, cholinesterase, HCV-viral load, viral subtypes, and 90K/Mac-2BP. On correlation of age and 90K/Mac-2BP levels, we found an apparent correlation that was proved rather to be a strong dependence of 90K/Mac-2BP concentrations on disease severity/duration, which increases with age. Multiple correlation analysis demonstrated the independent nature of 90K/Mac-2BP concentrations, underscoring the potential high utility of this new marker. Our data corroborate the potential of the scavenger receptor family protein 90K/Mac-2BP as an independent predictor of disease severity during HCV infection.

Adolescent↗

PubMed2000

Effect of estradiol on insulin secreting INS-1 cells overexpressing estrogen receptors.

BACKGROUND: Estrogen has been shown to have profound effects on insulin and glucose metabolism in vivo. Indeed, estrogens were recently shown to modulate ion channel and secretory activities in endocrine cells. DESIGN AND METHODS: To investigate whether estrogenic influences are caused by direct effects on pancreatic beta-cells, we equipped INS-1 insulinoma cells with estrogen receptors and monitored insulin content and Ca(2+) fluxes as well as basal and stimulated insulin secretion upon different stimuli including glucose, the Ca(2+) ionophore ionomycin, the Ca(2+) channel agonist BayK8644, the protein kinase C activator TPA, and the adenylate cyclase activator forskolin. RESULTS AND CONCLUSION: Our data reveal that estradiol has no significant direct effect on proliferation rate, insulin content, basal and stimulated insulin output as well as Ca(2+) fluxes of insulin secreting cells in vitro, indicating that in vivo responses to estrogen on insulin and glucose metabolism result from indirect betacytotropic effects.

Calcium↗

PubMed1999

Urinary excretion of apolipoprotein(a) fragments in type 1 diabetes mellitus patients.

High levels of plasma lipoprotein(a) [Lp(a)] represent an independent risk factor for cardiovascular morbidity; however, Lp(a) has not yet been identified as a risk factor for type 1 diabetic patients. Results from the limited number of available studies on plasma Lp(a) levels in relation to renal function in type 1 diabetes mellitus are inconclusive. We hypothesized that only type 1 diabetes mellitus patients with impaired renal function show increased plasma Lp(a) levels, due to decreased urinary apolipoprotein(a) [apo(a)] excretion. We therefore measured urinary apo(a) levels in 52 type 1 diabetes mellitus patients and 52 matched controls, and related the urinary apo(a) concentration to the plasma Lp(a) level, kidney function, and metabolic control. Our findings indicate that patients with incipient diabetic nephropathy as evidenced by microalbuminuria (20 to 200 microg/min) exhibit significantly higher plasma Lp(a) levels (median, 15.6 mg/dL) in comparison to normoalbuminuric patients (median, 10.3 mg/dL) and healthy controls (median, 12.0 mg/dL). Urinary apo(a) normalized to creatinine excretion was significantly elevated in both normoalbuminuric (median, 22.3 microg/dL) and microalbuminuric type 1 diabetic patients (median, 29.1 microg/dL) compared with healthy subjects (median, 16.0 microg/dL) and correlated significantly with Lp(a) plasma levels in both patient and control groups (P < .003). No correlation existed between the Lp(a) plasma level or urinary apo(a) concentration and metabolic control in type 1 diabetes mellitus patients. From these studies, we conclude that urinary apo(a) excretion is significantly increased in type 1 diabetic patients and correlates with plasma Lp(a) levels, and only type 1 diabetic patients with microalbuminuria have higher plasma levels of Lp(a) compared with patients with normoalbuminuria and healthy controls.

Adult↗

PubMed1999

The MYC dualism in growth and death.

Over-expression of the transcription factor c-Myc immortalizes primary cells and transforms in co-operation with activated ras. Therefore, c-myc is considered a proto-oncogene. Since its discovery c-Myc has been shown to render cells growth factor independent, accelerates passage through G1 of the cell cycle, inhibits differentiation and elicits apoptosis. Whereas the effects on immortalization, proliferation and inhibition of differentiation are in conceivable accordance with gain of function, as it is defined for a proto-oncogene, its pro-apoptotic activity disables a straight forward explanation of the physiological role of c-Myc and suggests a highly complex contribution during development. The recent accomplishments in c-Myc research shed some light on the difficile regulatory network which keeps check on c-Myc activity such as by binding to proteins some of which are transcription factors for non-c-Myc targets. Moreover, it was shown that genes are targeted by c-Myc depending on the sequence of flanking regions adjacent to the E-box or in dependence on the availability of binding partners which is most probably specific to the cellular context. Cdc25A and ornithine decarboxylase, both described to be c-Myc targets, have been brought forward as downstream effectors in the induction of proliferation under serum rich conditions, or in the induction of apoptosis when serum factors are limited. These genes seem to be regulated by c-Myc in a cell type-specific manner. H-ferritin, IRP2 and telomerase are the most recently discovered direct targets of c-Myc. The regulation of H-ferritin and IRP2 might explain the potential of c-Myc to promote proliferation and the regulation of telomerase could be responsible for the immortalizing properties of c-Myc. In the future, H-ferritin and telomerase have to be analyzed whether or not these genes are also Myc targets in other cell systems. Although the intense research efforts regarding the function of c-Myc last already two decades the role of this gene is still enigmatic.

Animals↗

PubMed1999

A community outbreak of Legionnaires' disease linked to hospital cooling towers: an epidemiological method to calculate dose of exposure.

BACKGROUND: From July to September 1994, 29 cases of community-acquired Legionnaires' disease (LD) were reported in Delaware. The authors conducted an investigation to a) identify the source of the outbreak and risk factors for developing Legionella pneumophila serogroup 1 (Lp-1) pneumonia and b) evaluate the risk associated with the components of cumulative exposure to the source (i.e. distance from the source, frequency of exposure, and duration of exposure). METHODS: A case-control study matched 21 patients to three controls per case by known risk factors for acquiring LD. Controls were selected from patients who attended the same clinic as the respective case-patients. Water samples taken at the hospital, from eight nearby cooling towers, and from four of the patient's homes were cultured for Legionella. Isolates were subtyped using monoclonal antibody (Mab) analysis and arbitrarily primed polymerase chain reaction (AP-PCR). RESULTS: Eleven (52%) of 21 case-patients worked at or visited the hospital compared with 17 (27%) of 63 controls (OR 5.0, 95% CI : 1.1-29). For those who lived, worked, or visited within 4 square miles of the hospital, the risk of illness decreased by 20% for each 0.10 mile from the hospital; it increased by 80% for each visit to the hospital; and it increased by 8% for each hour spent within 0.125 miles of the hospital. Lp-1 was isolated from three patients and both hospital cooling towers. Based on laboratory results no other samples contained Lp-1. The clinical and main-tower isolates all demonstrated Mab pattern 1,2,5,6. AP-PCR matched the main-tower samples with those from two case-patients. CONCLUSION: The results of our investigation suggested that the hospital cooling towers were the source of a community outbreak of LD. Increasing proximity to and frequency of exposure to the towers increased the risk of LD. New guidelines for cooling tower maintenance are needed. Knowing the location of cooling towers could facilitate maintenance inspections and outbreak investigations.

Adult↗

PubMed1999

Rubella virus-induced cytopathic effect in vitro is caused by apoptosis.

Rubella virus (RV) generally causes a mild disease but it is highly teratogenic when infection occurs during the first trimester of gestation. Under in vitro conditions, RV induces characteristic cytopathic changes on several cell lines, e.g. cell detachment from the monolayer and condensation of chromatin. The purpose of this study was to characterize RV-induced cell death and to determine the factors that might be involved in this process. Both acutely and persistently infected cells exhibited alterations characteristic of apoptosis, including DNA fragmentation, annexin V staining and reduced DNA content. UV-inactivated RV did not induce apoptotic cell death and expression of RV structural proteins in a transfected cell line was not sufficient to induce apoptosis, supporting the interpretation that replicating virus is necessary to provoke apoptosis. Both persistently infected and 24S-transfected cells retained their susceptibility to undergo apoptosis in response to either staurosporine or camptothecin. This indicates that RV does not block chemically induced apoptosis. The signals involved in RV-associated apoptosis appear to be independent of p53 and of the Bcl-2 gene family.

Animals↗

PubMed1999

[Immunologic and tumor biology aspects of placentation in humans].

In this survey, findings relating to the control of infiltration by the cytotrophoblast during human placentation are reviewed, with particular reference to immunology and tumour biology. Possible effects on pregnancy and parturition due to failure of the regulatory processes involved in placentation are discussed.

Female↗

PubMed1998

Radiotherapy in Ewing's sarcoma and PNET of the chest wall: results of the trials CESS 81, CESS 86 and EICESS 92.

PURPOSE: Treatment results and the pattern of relapse were evaluated in the multimodal treatment of Ewing's sarcomas of the chest wall. METHODS AND MATERIALS: In a retrospective analysis, 114 patients with non-metastatic Ewing's sarcoma of the chest wall were evaluated. They were treated in the CESS 81, CESS 86, or EICESS 92 studies between January 1981 and December 1993. The treatment consisted of polychemotherapy (VACA, VAIA, or EVAIA) and local therapy, either surgery alone (14 patients), radiotherapy alone (28 patients) or a combination of both (71 patients). The median follow-up was 46.6 months (range 5-170). A relapse analysis for all patients with local or combined relapses was performed. RESULTS: Overall survival was 60% after 5 years, event-free survival was 50%. Thirty-seven patients had a systemic relapse (32.4%), 11 patients had a local relapse alone (9.6%), and 3 patients had a combined local and systemic relapse (2.6%). The risk to relapse locally after 5 years was 0% after surgery alone, 19% after radiation alone, and 19% after postoperative irradiation. None of the 8 patients with preoperative irradiation have failed locally so far. With the introduction of central radiotherapy planning in CESS 86, local control of irradiated patients improved. Ten of 14 patients with local failure could be evaluated in the relapse analysis: 3 patients had an in-field relapse, 4 patients had a marginal relapse, 2 patients had a relapse outside the radiation fields, and 1 patient failed with pleural dissemination. Six treatment deviations were observed. CONCLUSION: Local control was best after surgery alone in a positively selected group of patients. Local control after radiation or combined radiation and surgery was good. With diligent performance of radiotherapy, it will be possible to further improve the results in the radiotherapy group.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1998

PKC-independent modulation of multidrug resistance in cells with mutant (V185) but not wild-type (G185) P-glycoprotein by bryostatin 1.

Bryostatin 1 is a new antitumor agent which modulates the enzyme activity of protein kinase C (PKC, phospholipid-Ca2+-dependent ATP:protein transferase, EC 2.7.1.37). Several reports have suggested that the pumping activity of the multidrug resistance gene 1 (MDR1)-encoded multidrug transporter P-glycoprotein (PGP) is enhanced by a PKC-mediated phosphorylation. It was shown here that bryostatin 1 was a potent modulator of multidrug resistance in two cell lines over-expressing a mutant MDR1-encoded PGP, namely KB-C1 cells and HeLa cells transfected with an MDR1-V185 construct (HeLa-MDR1-V185) in which glycine at position 185 (G185) was substituted for valine (V185). Bryostatin 1 is not able to reverse the resistance of cells over-expressing the wild-type form (G185) of PGP, namely CCRF-ADR5000 cells and HeLa cells transfected with a MDR1-G185 construct (HeLa-MDR1-G185). Treatment of HeLa-MDR1-V185 cells with bryostatin 1 was accompanied by an increase in the intracellular accumulation of rhodamine 123, whereas no such effect could be observed in HeLa-MDR1-G185 cells. HeLa-MDR1-V185 cells expressed the PKC isoforms alpha, delta and zeta. Down-modulation of PKC alpha and delta by 12-O-tetradecanoylphorbol-13-acetate (TPA) did not affect the drug accumulation by bryostatin 1. Bryostatin 1 depleted PKC alpha completely and PKC delta partially. In HeLa-MDR1-V185 cells, short-term exposure to bryostatin 1, which led to a PKC activation, was as efficient in modulating the pumping activity of PGP as long-term exposure leading to PKC depletion. Bryostatin 1 competed with azidopine for binding to PGP in cells expressing the MDR1-V185 and MDR1-G185 forms of PGP. It is concluded that bryostatin 1: i) interacts with both the mutated MDR1-V185 and the wild-type MDR1-G185; ii) reverses multidrug resistance and inhibits drug efflux only in PGP-V185 mutants; and iii) that this effect is not due to an interference of PKC with PGP. For gene therapy, it is important to reverse the specific resistance of a mutant in the presence of a wild-type transporter and vice versa. Our results show that it is possible to reverse a specific mutant PGP.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1998

Reversal of multidrug resistance by the staurosporine derivatives CGP 41251 and CGP 42700.

It has been shown previously that the staurosporine derivative CGP 41251, a specific inhibitor of protein kinase C (IC50 = 50 nM), exhibits antitumor activity and reverses mdr1 mediated multidrug resistance. At present, the compound is evaluated as an anticancer drug in clinical phase I trials. We compared the effects of CGP 41251 with CGP 42700, another staurosporine derivative, which exhibits low protein kinase C inhibiting activity (IC50 = > 100 microM). We found that in contrast to CGP 41251, CGP 42700 does not show antiproliferative activity in HeLa and KB cells in tissue culture (up to a concentration of 10 microM). We compared both compounds for their ability to reverse mdr1-mediated resistance in KB-C1 and in HeLa-MDR1 cells (transfected with the mdr1 gene). CGP 42700 is able to reverse mdr1-mediated resistance to a similar extent as CGP 41251. The intracellular accumulation of rhodamine 123 in KB-C1 cells following pretreatment with CGP 41251 for 30 min was higher than that following treatment with CGP 42700 if determined in medium without serum. However, quantitation of rhodamine efflux in an ex vivo assay using human CD8+ cells in serum showed that CGP 42700 is more effective in inhibiting the efflux of rhodamine 123 than CGP 41251. We conclude from our results that (1) CGP 42700 is more effective in reversal of multidrug resistance in serum than CGP 41251, indicating that the compound may be useful for treatment of patients, and (2) CGP 42700 does not inhibit protein kinase C and cell proliferation and, therefore, may be less toxic and elicit less side effects in humans than other chemosensitizers.

Antineoplastic Agents↗

PubMed1998

Fatty acid elongation in yeast--biochemical characteristics of the enzyme system and isolation of elongation-defective mutants.

Elongation of long-chain fatty acids was investigated in yeast mutants lacking endogenous de novo fatty acid synthesis. In this background, in vitro fatty acid elongation was dependent strictly on the substrates malonyl-CoA, NADPH and a medium-chain or long-chain acyl-CoA primer of 10 or more carbon atoms. Maximal activity was observed with primers containing 12-14 carbon atoms, while shorter-chain-length acyl-CoA were almost (octanoyl-CoA) or completely (hexanoyl-CoA, acetyl-CoA) inactive. In particular, acetyl-CoA was inactive as a primer and as extender unit. The Michaelis constants for octanoyl-CoA (0.33 mM), decanoyl-CoA (0.83 mM) lauroyl-CoA (0.05 mM), myristoyl-CoA (0.4 mM) and palmitoyl-CoA (0.13 mM) were determined and were comparable for fatty acid synthesis and elongation. In contrast, the affinity of malonyl-CoA was 17-fold lower for elongation (Km = 0.13 mM) than for the fatty acid synthase (FAS) system. With increasing chain length of the primer (> or = 12:0), fatty acid elongation becomes increasingly sensitive to substrate inhibition. Due to the activation of endogenous fatty acids, ATP exhibits a stimulatory effect at suboptimal but not at saturating substrate concentrations. In the yeast cell homogenate, the specific activity of fatty acid elongation is about 10-20-fold lower than that of de novo fatty acid synthesis. The same elongation activity is observed in respiratory competent and in mitochondrially defective cells. The products of in vitro fatty acid elongation are fatty acids of 15-17 or 22-26 carbon atoms, depending on whether tridecanoyl-CoA or stearoyl-CoA is used as a primer. In vitro, the elongation products are converted in part, by alpha-oxidation, to their odd-chain-length lower homologues or are hydrolyzed to fatty acids. In contrast, no odd-chain-length elongation products or very-long-chain fatty acids (VLCFA) shorter than 26:0 are observed in vivo. Hence, VLCFA synthesis exhibits a higher processivity in vivo than in the cell homogenate. In addition, the in vivo process appears to be protected against side reactions such as hydrolysis or alpha-oxidation. Yeast mutants defective in 12:0 or 13:0 elongation were derived from fas-mutant strains according to their failure to grow on 13:0-supplemented media. In vivo, 12:0 elongation was reduced to 0-10% of the normal level, while 16:0 elongation and VLCFA synthesis were unimpaired. It is concluded that yeast contains either two different elongation systems, or that the respective mutation interferes differentially with medium-chain and long-chain fatty acid elongation. The yeast gene affected in the elongation-defective mutants was isolated and, upon sequencing, identified as the known ELO1 sequence. It encodes a putative membrane protein of 32-kDa molecular mass with no obvious similarity to any of the known FAS component enzymes.

Acyl Coenzyme A↗

PubMed1998

The rubella virus putative replicase interacts with the retinoblastoma tumor suppressor protein.

In utero fetal infection of rubella virus (RV), a positive-stranded RNA virus, frequently induces birth defects if contracted in the first trimester of pregnancy. The underlying mechanism of RV-induced birth defects is not known. Birth defects are also common in certain DNA viral infections such as human cytomegalovirus (HCMV). During HCMV infection, one of its proteins interacts with a cell growth regulatory protein, the retinoblastoma protein (Rb) and stimulates DNA synthesis which is associated with chromosomal damage and cellular mitotic arrest. These affects have been implicated in HCMV induced teratogenesis. Since RV and HCMV both cause teratogenesis, we postulated that during RV infection, a virus-encoded protein might interact with Rb and affect fetal cell growth. In the present study, we have identified a known Rb-binding motif, L x C x E (LPCAE) in the carboxy-terminal half of the putative replicase (NSP90) of RV and demonstrated that the C-terminal region specifically binds to GST-Rb in vitro. Further, by coimmunoprecipitating NSP90 and Rb using specific antibodies to respective proteins, we have confirmed that NSP90 specifically binds to Rb in vivo as well. In addition, RV replication was shown to be less in null-mutant (Rb-/-) mouse embryonic fibroblast cells than in wild-type (Rb+/+) cells, suggesting a possible physiological role for this interaction. Thus, in facilitating RV replication, binding of NSP90 to Rb potentially alters the cell growth regulatory property of Rb, and this could be one of the initial steps in RV-induced teratogenesis.

Animals↗

PubMed1997

Azinyl and diazinyl hydrazones derived from aryl N-heteroaryl ketones: synthesis and antiproliferative activity.

A series of N-heteroaryl hydrazones derived from aryl N-heteroaryl or bis-N-heteroaryl methanones was prepared in search for potential novel antitumor agents. The stereochemistry of these compounds was established by means of NMR spectroscopy. Antiproliferative activity was determined in a panel of human tumor cell lines (CCRF-CEM, Burkitt's lymphoma, HeLa, ZR-75-1, HT-29, and MEXF 276L) in vitro. Generally, the new compounds were found to be more potent (IC50 = 0.011-0.436 microM) than the ribonucleotide reductase inhibitor hydroxyurea (IC50 = 140 microM). Most of the compounds exhibited the highest activity against Burkitt's lymphoma with an IC50 of 0.011-0.035 microM. [14C]Cytidine incorporation into DNA was quantitated for selected hydrazones (Z-A, E-1, Z-3, Z-4, E-5, Z-5, E-13, E-18, Z-19, Z-24, and E-26) as a measure of the inhibition of ribonucleotide reductase in Burkitt's lymphoma cells. The E-configurated compounds were found to inhibit [14C]cytidine incorporation to a greater extent (IC50 = 0.67-5.05 microM) than the Z-isomers (IC50 = 7.20 to > 10 microM). Principal component analysis of the IC50 values obtained for inhibition of cell proliferation revealed that the cell lines tested can be grouped into three main families showing different sensitivities toward the compounds in our series [(i) CCRF-CEM, Burkitt's lymphoma, and Hela; (ii) HT-29; and (iii) MEXF 276 L].

Antineoplastic Agents↗