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Biomedical subjects

M D'Incalci

Publications and source records attributed to M D'Incalci.

301 records · Page 17Linked to original sources
PubMedDate not supplied

Cell cycle-related phosphatases CDC25A and B expression correlates with survival in ovarian cancer patients.

Alterations in cell cycle regulating proteins are common in many cancer types. Recent data suggest a possible link between CDC25 phosphatases overexpression and malignancy. Our objective was to evaluate the expression of the three cell cycle-related phosphatases CDC25A, CDC25B and CDC25C in patients with ovarian cancer. All the patients had a minimal follow up of three years. CDC25A, CDC25B and CDC25C expression were investigated by immunohistochemistry in 106 patients with ovarian cancer. CDC25A and CDC25B were found expressed in almost all the samples analyzed, while CDC25C was undetectable in more than 80% of the patients. The low evaluable data on CDC25C expression, did not allow any association between the expression of this phosphatase and prognosis. The expression of CDC25A and CDC25B showed some evidences of association with a poor prognosis (p = 0.034 and p = 0.058 respectively). This relationship was independent of other factors such as tumor grade, histotype, stage and residual tumor after surgery. In the same patients the examined parameters (residual tumor, grade, stage and histotype) did show the expected relation with survival. The results indicate that high CDC25A and CDC25B expression is related to a worse prognosis in ovarian cancer patients. CDC25 phosphatases expression can be regarded as a possible prognostic factor for ovarian cancer and these proteins should be evaluated as potential molecular targets of novel drugs against this human neoplasm.

Antineoplastic Combined Chemotherapy Protocols↗
PubMedDate not supplied

Changes in gene expression profile induced by the anticancer agent Aplidine in Molt-4 leukemic cell lines.

Microarray technique was employed to study differences in gene expression profile induced by Aplidine treatment in the Molt-4 human leukemic T cell line. Aplidine is a novel marine compound purified from caribbean tunicate (sea squirt) Aplidium Albicans. Despite promising anti-tumor activity, few data are available on its mechanism of action. Exponentially growing cells were treated with Aplidine concentrations close to its 5IC50 for 1 hour and RNA samples collected after 0.5, 1, 6 and 24 hours of recovery in drug free medium. 32P labelled cDNAs were hybridized against Atlas Human Cancer arrays onto which 588 cDNAs were spotted. Genes involved in different cellular pathways, (such as growth factors, signal transduction or transcription factors) were found modulated by the drug. Even if the data obtained in the present study cannot be conclusive, several hypothesis on Aplidine's mechanism of action are indicated that will be the subject of future studies.

Anticarcinogenic Agents↗
PubMedDate not supplied

Tumour levels of O6-alkylguanine-DNA-alkyltransferase and sensitivity to BCNU of human xenografts.

Tumour levels of O6-alkylguanine-DNA-alkyltransferase (O6 AT) and glutathione content (GSH) were correlated with 1, 3-Bis (2-chloroethyl)-1-nitrosourea (BCNU) sensitivity in two human ovarian cancer xenografts (HOC8 and HOC18) and in two human glioblastoma xenografts (HG12 and HG15). HOC8 and HOC18, which were not responsive to BCNU treatment, showed O6 AT levels 14 and 23-fold higher than HG12 that was moderately sensitive to the same BCNU treatment. HG15, which was more sensitive to BCNU than HG12, showed significantly lower O6 AT levels. GSH levels were similar in all tumor xenografts. These data further stress the importance of O6 AT level as a relevant parameter for nitrosourea response in human tumours.

Animals↗
PubMedDate not supplied

O6-methylguanine and temozolomide can reverse the resistance to chloroethylnitrosoureas of a mouse L1210 leukemia.

Using L1210 and a subline resistance to chloroethylnitrosoureas (L1210/BCNU), we found that the resistance to 1-(2-chloroethyl)-1-nitrosourea (CNU) or to diethyl-1-3-(2-chloroethyl)-3-nitrosoureido ethyl phosphonate (fotemustine) can be reversed by a pretreatment with O6-methyl Guanine (O6-mGua) or temozolomide. In L1210/BCNU but not in L1210 the pretreatment with O6mGua caused an increased peak level of CNU-induced DNA-interstrand crosslinks. We then evaluated whether the resistance to BCNU could be counteracted in vivo by i.p. O6mGua treatment of L1210/BCNU bearing mice. The results were negative due to the fact that O6mGua, which was not toxic when given alone, caused a high toxicity when associated with BCNU.

Animals↗
PubMedDate not supplied

Flavone acetic acid pharmacokinetics in nude mice.

The pharmacokinetics of flavone acetic acid (FAA) were comparatively studied in Balb-c mice and in immunocompetent nude mice treated with i.v. doses of 100 and 300 mg/kg. In both strains of mice, FAA kinetics appear to be dose-dependent, since the AUC values increased disproportionally to the dose. FAA protein binding and the pattern of distribution were similar in Balb-c and nude mice, the highest drug concentrations being found in liver and small intestine and the lowest in brain. Renal excretion appears to be the major route of FAA elimination in both strains, accounting for about 75% of the total drug administered after a dose of 100 mg/kg and 50-60% after a dose of 300 mg/kg. We conclude that FAA pharmacokinetics are comparable in Balb-c and nude mice so that the previously investigated FAA dosage schedules in inbred mice can also be employed in nude mice bearing human tumors.

Animals↗
PubMedDate not supplied

Identification of microsomal metabolites of spirogermanium.

In the present study we report on the identification of two novel microsomal metabolites of the investigational anticancer agent Sprigermanium (NSC-192965). The two metabolites were isolated after incubation of Spirogermanium with fortified rat liver microsomes. Mass spectrometry studies indicate that one of them, formed in major quantities, is hydroxy Spirogermanium. The other metabolite appears to correspond to bis-desmethylated Spirogermanium.

Animals↗
PubMedDate not supplied

Antitumor activity of the novel nitrosourea S10036 in rodent tumors.

The activity of the novel anticancer agent diethyl 1-3-(chloroethyl)-3-nitrosoureido ethyl phosphonate (S10036) was investigated on several rodent tumors. S10036 showed a good efficacy, comparable to that of the anticancer agent BCNU, against i.p transplanted P388 and L1210 leukemias. S10036 was very effective against the primary tumor and metastases of i.m transplanted M5076 reticular cell sarcoma of the mouse and against subline A of the Walker carcinoma of the rat. It was inactive against rodent tumors resistant to BCNU such as L1210/BCNU, ICIG-Ci4 murine fibrosarcoma and the Walker carcinoma subline B in the rat.

Animals↗
PubMedDate not supplied

Pharmacokinetics of hexamethylmelamine and pentamethylmelamine in mice.

Plasma pharmacokinetics of hexamethylmelamine (HMM) and pentamethylmelamine (PMM) were investigated after ip administration of doses of 50 or 100 mg/kg to M5076/73A ovarian tumor-bearing C57BL/6J female mice. The half-life of HMM was 44.5-49 mins; the half-life of PMM was 7.6-8.7 mins. The area under the concentration-versus-time curve (AUC) was also much higher for HMM than for PMM. The AUC for the metabolite N2,N2,N4,N6-tetramethylmelamine (TMM) was seven to ten times higher than that of the parent compounds. After incubation with mouse liver microsomes and cofactors, the rates of metabolism of HMM and PMM were essentially the same. Plasma protein binding was 94%, 71%, and 50% for HMM, PMM, and TMM, respectively.

Altretamine↗
PubMedDate not supplied

Effect of G:C-->A:T transition, potentially arising from O6-guanine alkylation, in the transcription regulation of c-fos serum response element.

O6-meGs, if not repaired before cell undergo DNA synthesis, can cause erroneous pairing of thymine resulting in a G:C-->A:T transition, after the next DNA replication. It is known that the presence of O6-meG in promoter sequences inhibits the specific binding of transcription factors. Little is known on the effect of G:C-->A:T transitions on this binding. c-fos SRE was used as a model to study the effect of different G:C-->A:T transitions (at the positions -305, -306, -316, -319 and -320) in terms of SRE specific DNA-binding and functional ability to activate transcription of a reporter gene. The electromobility shift assay and a transient transfection assay were used. The G:C-->A:T transition at -320 caused 92% inhibition, while mutations at the positions -305, -306, -316 and -319 caused respectively 55, 43, 19 and 44% inhibition. The findings indicate that some G:C-->A:T transitions, potentially arising from O6-guanine methylation, can impair the regulation of c-fos transcription.

3T3 Cells↗