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C Paoletti

Publications and source records attributed to C Paoletti.

At least 19 recordsLinked to original sources
PubMed2005

Risk of melanoma following adulthood cancer: a case-control study.

Melanoma is a severe skin cancer related to sun exposure. Whether this malignancy is linked to exposure to ionising radiation during adulthood is still controversial. This case-control study examined the risk of melanoma following treatment for an adulthood first malignant neoplasm (FMN). Cases were patients who presented with cutaneous melanoma after a first cancer in adulthood. Controls (3 per case) were patients free of melanoma, matched for age, duration of follow-up since the FMN, type of FMN, and followed in the same institution. A total of 57 cases and 171 controls were included. In the final multivariate analysis, no risk of melanoma was associated with radiotherapy (odds ratio (OR) for 1 Gy = 1.01, 95% confidence interval (95%CI) 0.96-1.07) nor hormonotherapy, whereas chemotherapy use (OR = 2.3, 95%CI 0.93-5.6) and having a history of familial cancer (OR = 2.8, 95%CI 1.3-5.9) exhibited a nearly significant risk. In conclusion, unlike the evidence for risk of exposure to ionising radiation during childhood, we did not substantiate a risk for association of melanoma with exposure to ionising radiation during adulthood. The risk associated with chemotherapy should justify the implementation of skin surveillance for early detection of melanoma in these patients.

Adolescent↗
PubMed1996

Effects of CYP2D6 activity and tobacco on larynx cancer risk.

The genetically determined capacity of the cytochrome P450 CYP2D6 is suspected to be involved in the activation of tobacco carcinogens. From a multicentric case-control study carried out to analyze the interaction between host and environmental factors on tobacco-related cancers, we reported recently that the effect of tobacco on lung cancer risk rose with increasing CYP2D6 activity, and the effect of CYP2D6 activity rose with increasing tobacco consumption. The aim of the present report was to investigate whether results on lung cancer could be observed for larynx cancer, from a study on 140 cases and 157 controls. A weak interaction between increasing levels of both CYP2D6 activity and average daily consumption of tobacco was found (P = 0.12). The only significant interaction between these two factors was observed when CYP2D6 activity was considered with the two conventional phenotypes (P < 0.05). A dose-response effect of tobacco on larynx cancer risk was found only among one-third of the smokers with the highest level of CYP2D6 activity, and CYP2D6 was a risk factor only among heavy smokers. The highest risk for larynx cancer was then observed among smokers having both the highest levels of CYP2D6 activity and daily consumption of tobacco. The interaction between CYP2D6 activity and tobacco was weaker for larynx cancer than that reported previously for lung cancer. However, the similarities in the results found for these two cancers, i.e., a greater effect of tobacco among smokers with the highest CYP2D6 activity, reinforce the hypothesis that this activity could modify the effect of tobacco on cancer risk.

Aged↗
PubMed1994

[In vitro stimulation by ellipticine derivatives of DNA cleavage induced by DNA topoisomerase II: a structure-activity relationship].

Ellipticines are intercalating planar polycyclic aromatic molecules that display antitumor activity. The cytotoxicity of these compounds is related to the presence of an hydroxy group at position 9 of the pyridocarbazole ring system and to their interaction with DNA topoisomerase II. The ability of 13 ellipticine derivatives to stabilize the topoisomerase II-DNA covalent complex in vitro is reported. The following observations emerge from our structure-activity relationship study: i) the hydroxy group at position 9 is essential for stabilizing the covalent complex, ii) the replacement of the methyl group at position 5 by an ethyl group (EPC) enhances the complex stabilization. The interaction of EPC and three other ellipticine analogues with DNA shows that the covalent complexes which are most stable have the lowest drug-DNA binding constants. In addition our study suggests that ellipticines induce covalent complex stabilization by a cooperative mechanism. A model is proposed to explain this stabilization by ellipticines. This study supports the idea that topoisomerase II is the primary target involved in the mechanisms of action of ellipticines.

Antineoplastic Agents↗
PubMed1993

The localization of topoisomerase II cleavage sites on DNA in the presence of antitumor drugs.

Type II topoisomerase are enzymes that break and religate DNA phosphodiester bonds while crossing over DNA strands and altering DNA topology. They also are structural proteins that play a role in the spatial organization of chromatin and are involved in several crucial biological functions, such as DNA replication and transcription, chromosome segregation and recombination. Many drugs interfere with type II topoisomerases and can be assigned to two groups. Coumarin derivatives and synthetic quinolones act at the level of ATP binding or hydrolysis and are used for controlling bacterial infections. Drugs belonging to the second group produce DNA lesions by trapping a "cleavable complex" consisting of the normal transient topoisomerase II-DNA reaction intermediate in which the enzyme and the DNA are joined by two covalent bonds. There are four main categories of antitumour drugs that form cleavable complexes in eukaryotes: acridines, anthracyclines, ellipticines and epipodophyllotoxins. These drugs are cytotoxic and many--but not all--are endowed with antitumoral properties. The mechanisms of this pharmacological activity are not understood. Topoisomerase II-induced DNA breaks generated from cleavable complexes display different levels of cytotoxicity depending on their localization on DNA. The primary structure of DNA is not the only parameter that determines this localization. The spatial organization of the enzyme-DNA complex and both the topology and the structure of the underlying chromatin fiber constitute additional critical factors. It, therefore, may be unrealistic to expect that the actual pharmacological potency of antitumor drugs that act on type II topoisomerases can be accurately predicted solely on the basis of simple in vitro test tube experiments carried out using pure enzymes and naked DNA.

Antineoplastic Agents↗
PubMed1992

A carboline derivative as a novel mammalian DNA topoisomerase II targeting agent.

The DNA intercalating, ellipticine analog drug, 5,11-dimethyl-5H-indol[2,3-b]quinoline, is able to stabilize in vitro the topoisomerase II-DNA cleavable complex and to induce DNA breaks in BPV I episome in rat fibroblasts. Cytotoxicity studies with DC3F cells resistant to ellipticine strongly suggest that topoisomerase II is a cellular target involved in the mechanism of cytotoxic action of this carboline derivative.

Amsacrine↗
PubMed1992

Does cruciform DNA provide a recognition signal for DNA-topoisomerase II?

Topoisomerase II displays higher affinity for supercoiled DNA compared to the same relaxed DNA. Moreover, cruciform structures are formed in topologically constrained DNA. Here we report that, using S1 nuclease experiments on supercoiled DNA, hairpin structures are located close to numerous topoisomerase II cleavage sites on the BPV I genome. Therefore, DNA secondary structure may play a role in the recognition mechanism of DNA by topoisomerase II.

Base Sequence↗
PubMed1992

Stimulation of topoisomerase II-mediated DNA cleavage by ellipticine derivatives: structure-activity relationship.

Ellipticines are aromatic compounds that intercalate between DNA base pairs and display significant antitumor activity. The cytotoxicity of these compounds is mediated by DNA topoisomerase II, and the presence of a hydroxy group at position 9 of the pyridocarbazole ring system of ellipticines has been found to be essential for high levels of cytotoxicity. The ability of 13 ellipticine derivatives to stabilize the topoisomerase II-DNA covalent complex in vitro was studied, and the data obtained with five pairs of hydroxylated and nonhydroxylated analogues indicate that the hydroxy group at position 9 plays a crucial role in the stabilization of the complex. The influence, upon the complex stabilization, of various substituents at positions 1, 2, 5, and 6 of the pyridocarbazole ring system was investigated. The interaction with DNA of four ellipticine derivatives was studied in the topoisomerase II standard medium. Results suggest that the degree of unwinding might be a determinant of topoisomerase II-DNA-drug complex stability. In addition, the 5-ethyl derivative was observed to induce covalent complex stabilization by a cooperative mechanism.

DNA Damage↗
PubMed1992

[Potentiation of the antitumoral effect of electrochemotherapy by immunotherapy with allogeneic cells producing interleukin 2].

Electrochemotherapy (ECT) is a new antitumour treatment which consists of delivering electric pulses to the tumour a few minutes after an intravenous injection of bleomycin. The antitumour efficacy of ECT is increased by local injections of interleukin 2 (IL2) in the oedema which appears at the site of the treated tumours. We have shown that tumour cells inoculated in syngeneic mice are rejected if IL2 secreting allo- or xenogeneic cells are co-injected with tumour cells. We report here the large increase of ECT therapeutical efficacy when allogeneic cells secreting IL2 are injected into the peri-tumoural oedema.

Animals↗
PubMed1992

A randomised 2 x 2 factorial design to evaluate different smoking cessation methods.

A study with a 2 x 2 factorial design was performed to evaluate the effectiveness of acupuncture, of nicotine gum and the effect of the association on smoking cessation. After a one-year follow-up period, the success rates were in the same order of magnitude for nicotine gum (active treatment: 10%, placebo: 8%) group and for acupuncture (active treatment: 8%, placebo: 10%) group.

Acupuncture Therapy↗
PubMed1991

Sequence requirements for mammalian topoisomerase II mediated DNA cleavage stimulated by an ellipticine derivative.

Various antitumor drugs stabilize DNA topoisomerase II-DNA transient covalent complexes. The complexes distribution along pBR322 DNA was shown previously to depend upon the nature of the drug (Tewey et al. (1984) Science 226, 466-468). The position in pBR322 of DNA cleavage by calf DNA topoisomerase II for 115 such sites stabilized by an ellipticine derivative and the relative frequency of cleavage at most of these sites were determined. The nucleotide sequence surrounding the 25 strongest sites was analyzed and the following ellipticine specific consensus sequence was deduced: 5'-ANCNT(A/G)T.NN(G/C)N(A/G)-3' where cleavage occurs at the indicated mark. A thymine is always present at the 3' end of at least one strand of the strong cleavage sites, and the dinucleotide AT or GT at the 3' end of the break plays a major role in the complex stabilisation. The predictive value of cleavage of the consensus was tested for two regions of SV40 DNA and cleavage was indeed detected at the majority of the sites matching the consensus. Some complexes stabilized by ellipticine are resistant to salt dissociation and this property seems to be correlated with the presence of symmetrical sequences in the cleavage site with a center of symmetry staggered relatively to the center of symmetry of cleavage.

Animals↗
PubMed1991

Bis(pyrrolecarboxamide) linked to intercalating chromophore oxazolopyridocarbazole (OPC): selective binding to DNA and polynucleotides.

We have investigated some properties related to interaction with DNA and recognition of AT-rich sequences of netropsin-oxazolopyridocarbazole (Net-OPC) (Mrani et al., 1990), which is a hybrid groove-binder-intercalator. The hybrid molecule Net-OPC binds to poly[d(A-T)] at two different sites with Kapp values close to 7 x 10(6) and 6 x 10(8) M-1 (100 mM NaCl, pH 7.0). Data obtained from melting experiments are in agreement with these values and indicate that Net-OPC displays a higher binding constant to poly[d(A-T)] than does netropsin. On the basis of viscometric and energy transfer data, the binding of Net-OPC to poly[d(A-T)] is suggested to involve both intercalation and external binding of the OPC chromophore. In contrast, on poly[d(G-C)], Net-OPC binds to a single type of site composed of two base pairs in which the OPC chromophore appears to be mainly intercalated. The binding constant of Net-OPC to poly[d(G-C)] was found to be about 350-fold lower than that of the high-affinity binding site in poly[d(A-T)]. As evidenced by footprinting data, Net-OPC selectively recognizes TTAA and CTT sequences and strongly protects the 10-bp AT-rich DNA region 3'-TTAAGAACTT-5' containing the EcoRI site. The binding of Net-OPC to this sequence results in a strong and selective inhibition of the activity of the restriction endonuclease EcoRI on the plasmid pBR322 as substrate. The extent of inhibition of the rate constant of the first strand break catalyzed by the enzyme is about 100-fold higher than the one observed in the presence of netropsin under similar experimental conditions.

Base Sequence↗
PubMed1991

Electrochemotherapy potentiation of antitumour effect of bleomycin by local electric pulses.

In cell culture the cytotoxicity of some anticancer drugs, especially bleomycin, can be greatly enhanced by exposing cells to non-cytotoxic electric pulses. Nude or conventional mice bearing subcutaneous transplanted tumours were treated with intramuscular doses of bleomycin followed by local delivery of electric pulses similar to those used in vitro. Tumors were reduced and even eradicated after this electrochemotherapy. Thus the antitumour effects of bleomycin in mice can be considerably potentiated by local electric pulses.

Animals↗
PubMed1991

Electrochemotherapy of spontaneous mammary tumours in mice.

Electrochemotherapy delivers external electric pulses to the tumour site to induce local potentiation of the antitumour activity of intramuscular injections of bleomycin. C3H/Bi mice with spontaneous mammary carcinomas received weekly injections of 50 micrograms bleomycin followed by electric pulses 30 min later. All the 38 tumours treated exhibited at least a partial regression. 23 complete remissions were observed, 3 of which were cures. One difficulty in assessing the cure rate in this model is that frequent parallel or sequential tumours cause early death. Electrochemotherapy appears similarly efficient in spontaneous tumours as in previously studied transplanted tumours.

Animals↗
PubMed1991

Heterocyclic quinones. 17. A new in vivo active antineoplastic drug: 6,7-bis(1-aziridinyl)-4-[[3-(N,N-dimethylamino)propyl]amino]-5,8- quinazolinedione.

A series of heterocyclic quinones, 6-substituted and 6,7-disubstituted 4-(alkylamino)-5,8-quinazolinediones, have been synthesized in order to evaluate their in vitro cytotoxicity on L1210 leukemia cells. Among 14 derivatives that have been prepared and studied for the structure-activity relationship, the most potent cytotoxic compound on L1210 leukemia cells was the 6,7-bis(1-aziridinyl)-4-[[3-(N,N-dimethylamino)propyl]amino]-5,8- quinazolinedione (24). This compound has been tested with the use of a cell-image processor on MCF-7 human mammary and HBL human melanoma cell lines. The results show that compound 24 influences cell proliferation and blocks both cells lines in the S phase. In vivo antineoplastic activity of compound 24 has been demonstrated on a broad spectrum of murine experimental models, but it was found highly toxic and produced long-delayed deaths.

Animals↗
PubMed1991

Comparison of anti-RNA properties of normal and ellipticine functionalized alpha and beta-oligonucleotides.

RNA is not cleaved as a consequence of the binding of RNase H to the duplex between RNA and a complementary alpha-oligodeoxyribonucleotide (oligo). In consequence targets have been selected which do not a priori require the action of RNase H to inhibit genetic expression. Two models have been used: The Friend Murine Leukemia Virus (F-MuLV) and the synthesis of rabbit beta globin.alpha-oligos trigger specific inhibitions in both systems. The functionalisation in 5' with the intercalating agent 9-NH2-ellipticine renders the oligos resistant to degradation and allows a direct action on cells.

Animals↗
PubMed1991

[Electrochemotherapy, a new antitumor treatment: first clinical trial].

Electrochemotherapy (ECT) is a new antitumor treatment which consists in delivering electric pulses to the tumor some minutes after an intravenous injection of bleomycin. We report here the first clinical trial of ECT, applied to patients with permeation nodules of head and neck squamous carcinomas. ECT was well tolerated by patients, no serious incident occurred and a clear antitumor efficiency was found.

Bleomycin↗
PubMed1991

[Evaluation of cerebral blood flow in severe brain injuries by SVO2 measurement in the internal jugular vein].

The purpose of the present study was to assess the value of jugular oxyhemoglobin saturation percent (SvO2) in predicting cerebral blood flow (CBF). SvO2 and CBF were measured in 25 adults with acute brain trauma (Glasgow Coma Scale < 8). From the data a classification of CBS and SvO2 was developed: in the first group of patients the presence of cerebral ischemia could be identified in the presence of low CBF (< 40 ml/min/100g) and a low SvO2. In the second group he CBF is closely coupled to and regulated by the cerebral metabolic rate of oxygen (CMRO2) and values of SvO2 are intermediate. In the third group hyperaemia was defined as both an increase of SvO2 and CBF (> 60ml/min/100g) and a decrease of CMRO2. The SvO2 was measured in 18 of these 25 patients following 1) intravenous infusion of mannitol (1 g.kg-1) and hyperventilation (PCO2 = 3.4 kPa). The data suggest that there is no correlation between SvO2 and CBF, but a reliable estimates of CBF may be made from SvO2 measurement after mannitol and hyperventilation.

Blood Flow Velocity↗