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Biomedical subjects

G Cassinelli

Publications and source records attributed to G Cassinelli.

At least 19 recordsLinked to original sources
PubMed2004

Antitumour and antiangiogenic effects of IDN 5390, a novel C-seco taxane, in a paclitaxel-resistant human ovarian tumour xenograft.

IDN 5390 is a novel C-seco taxane analogue selected for preclinical development on the basis of its antimotility activity on endothelial cells, antitumour efficacy in a large panel of human tumour xenografts and high tolerability in mouse. On the basis of oral availability, IDN 5390 is suitable for protracted administration schedules. Such a treatment schedule has been reported as the most appropriate to exploit the antiangiogenic effects of cytotoxic drugs. An ability to downregulate angiogenesis-related growth factors in tumour cells has been described for IDN 5390. The aim of the study was to investigate the antitumour and antiangiogenic potential of oral IDN 5390 on a human ovarian carcinoma xenograft, the INT.ACP/PTX, resistant to paclitaxel (PTX). Such tumour line was derived in vivo from a cisplatin-resistant tumour line, the A2780/DDP, which is sensitive to PTX. Compared to the parental cells, INT.ACP/PTX cells exhibited a high level of Pgp expression, resulting in a reduced in vitro sensitivity to both PTX and IDN 5390. The INT.ACP/PTX tumour xenograft was still resistant to PTX, but responsive to IDN 5390, when delivered per os, by a daily prolonged schedule. A direct effect on tumour cells, allowed by the high tolerability of the compound in mouse, cannot be excluded in vivo. Immunohistochemical analysis indicated a significant reduction of microvessel density in IDN 5390-treated tumours, lasting till 7 days after the last drug administration. Thus, a prolonged inhibitory effect on tumour angiogenesis is consistent with the persistent growth control of INT.ACP/PTX tumour achieved by IDN 5390. On the contrary, the low tolerability and the limited oral availability of conventional taxanes do not allow an easy feasibility of such treatment regimen. Thus, the tolerability profile of IDN 5390 in preclinical systems and its efficacy in PTX-resistant tumours support the therapeutic interest for its clinical development, with particular attention to oral daily prolonged schedules.

Angiogenesis Inhibitors↗
PubMed2004

Induction of apoptosis and stress response in ovarian carcinoma cell lines treated with ST1926, an atypical retinoid.

To understand the molecular mechanisms mediating apoptosis induction by a novel atypical retinoid, ST1926, the cellular response to drug treatment was investigated in IGROV-1 ovarian carcinoma cells carrying wild-type p53 and a cisplatin-resistant p53 mutant subline (IGROV-1/Pt1). Despite a similar extent of drug-induced DNA strand breaks, the level of apoptosis was substantially higher in p53 wild-type cells. p53 activation and early upregulation of p53-target genes were consistent with p53-dependent apoptosis in IGROV-1 cells. Stress-activated protein kinases were activated in both cell lines in response to ST1926. This event and activation of AP-1 were more pronounced in IGROV-1/Pt1 cells, in which the modulation of DNA repair-associated genes suggests an increased ability to repair DNA damage. Inhibition of JNK or p38 stimulated ST1926-induced apoptosis only in IGROV-1 cells, whereas inhibition of ERKs enhanced apoptosis in both the cell lines. Such a pattern of cellular response and modulation of genes implicated in DNA damage response supports that the genotoxic stress is a critical event mediating drug-induced apoptosis. The results are consistent with apoptosis induction through p53-dependent and -independent pathways, regulated by MAP kinases, which likely play a protective role.

Adamantane↗
PubMed2003

IDN 5390: an oral taxane candidate for protracted treatment schedules.

The recognition of the antiangiogenic properties of taxanes provides a basis for novel therapeutic approaches. A prolonged exposure to low drug concentrations has been proposed to be the most suitable approach to exploit the antiangiogenic potential of cytotoxic agents. Such schedule is required to target preferentially slowly dividing endothelial cells. The protracted use of taxanes could benefit from the availability of a taxane endowed with a favourable tolerability profile. Among compounds of a novel series of C-seco taxanes, IDN 5390 was originally selected on the basis of its potent antimotility activity and poor cytotoxicity on endothelial cells. The aim of the study was to investigate the preclinical pharmacologic profile of IDN 5390 in a variety of human tumour xenografts, including ovarian and colon carcinoma and a glioblastoma. IDN 5390, delivered by s.c. injection, daily for 5 days per week, exhibited a high activity against all tumours investigated (tumour growth inhibition was always >85%) in the range of well-tolerated doses. The maximum tolerated dose/injection (MTD), with no signs of systemic or local vesicant toxicity, was 120 mg kg(-1). In contrast, paclitaxel, delivered according to the same schedule, exhibited a variable antitumour efficacy associated with a substantial local toxicity (MTD=10 mg kg(-1)). Considering the remarkable efficacy of IDN 5390 delivered s.c. by protracted treatment schedule, the oral route of administration was further investigated, as the most suitable for daily treatment. Indeed, a good bioavailability of oral IDN 5390 was found. Oral IDN 5390 maintained a substantial efficacy against human tumour xenografts, including paclitaxel-resistant tumours, without loss of potency with respect to s.c. administration. In conclusion, the therapeutic advantages of IDN 5390, over paclitaxel, in protracted daily treatment schedules are represented by the oral efficacy and the high tolerability, which are favourable features to exploit the antiangiogenic potential and to design combinations with other effective agents.

Administration, Oral↗
PubMed2003

Inactivation of Ret/Ptc1 oncoprotein and inhibition of papillary thyroid carcinoma cell proliferation by indolinone RPI-1.

Genetic alterations causing oncogenic activation of the RET gene are recognized as pathogenic events in papillary and medullary thyroid carcinomas. Inhibition of Ret oncoprotein functions could thereby represent a specific therapeutic approach. We previously described the inhibitory activity of the 2-indolinone derivative RPI-1 (formerly Cpdl) on the tyrosine kinase activity and transforming ability of the products of the RET/PTC1 oncogene exogenously expressed in murine cells. In the present study, we investigated the effects of RPI-1 in the human papillary thyroid carcinoma cell line TPC-1 spontaneously harboring the RET/PTC1 rearrangement. Treatment with RPI-1 inhibited cell proliferation and induced accumulation of cells at the G2 cell cycle phase. In treated cells, Ret/Ptc1 tyrosine phosphorylation was abolished along with its binding to Shc and phospholipase C(gamma), thereby indicating abrogation of constitutive signaling mediated by the oncoprotein. Activation of JNK2 and AKT was abolished, thus supporting the drug inhibitory efficacy on downstream pathways. In addition, cell growth inhibition was associated with a reduction in telomerase activity by nearly 85%. These findings in a cellular context relevant to the pathological function of RET oncogenes support the role of Ret oncoproteins as useful targets for therapeutic intervention, and suggest RPI-1 as a promising candidate for preclinical development in the treatment of thyroid tumors expressing RET oncogenes.

Animals↗
PubMed2003

[Appendiceal carcinoid: report of 3 clinical cases and review of the literature].

The Authors report three cases of appendiceal carcinoids, found during appendectomy for acute appendicitis during the last 15 years. Appendiceal carcinoid is a rare neoplasm, more frequent in females age ranging between 20 and 29 years. Lack of symptoms explains the occasional diagnosis of this disease. The prognosis is related mostly to the size of the tumor, local and lymphatic invasion, presence of metastases, localization inside the appendix, histological type and age of the patient. Therapy is mainly surgical and consists of appendectomy and right colectomy according to different criteria which are being discussed in this article.

Adult↗
PubMed2003

[MALT lymphoma of the gastrointestinal tract: description of clinical cases and review of the literature].

MALT-lymphomas are tumors of the mucosa associated lymphoid tissue, without primitive involvement of lympho nodes and spleen. They are located preferentially in the gastroenteric tract specially in the stomach (27%), but they may occur also in the respiratory and urinary tracts. There is a very well known link between MALT-omas and Hp infection, not only in the gastroenteric tract, but also in other sites. Moreover eradication of Helicobacter pylori can, in some cases, contribute to achieve the complete remission of the tumor. In this article the Authors report three cases of MALT-lymphomas: two of the stomach and one of the jejunum-ileum. Diagnosis is based on instrumental tests according to the involved tract and endoscopy of the upper digestive tract associated with biopsies more specific in case of gastric involvement; yet bioptic samples show a more significative incidence of false negative due to the extramucosal site of tumor. In these cases, a correct diagnosis will be obtained only through histologic examination of the surgical specimen. Surgery obtains good results in early stages, playing also a central role in palliation in association with radio- and chemotherapy. In case of low-grade B MALT-lymphomas of the stomach and in IE stages, eradication of Helicobacter pylori can, in 70-90% of cases, reduce the extension of the lymphocytic infiltration.

Aged↗
PubMed2002

[Primary gastric lymphoma: a case report].

In this case report the Authors describe a case of primary gastric lymphoma in a 62 years old patient who presented with dyspepsia and weigh loss. Primary gastric lymphoma is a rare neoplasm which of 1-10% of the malignant gastric neoplasms in the gastroenteric tract. The clinic presentation is usually aspecific. The infection by H. pylori is a factor of predisposition for this kind of disease. The diagnostic pathway consists in x-ray examination of the gastrointestinal tract, the endoscopy with biopsies, the computerized tomography and the echo-endoscopy. However obtaining a preoperative diagnosis is often difficult because of the submucosal localization of the lymphoma. There is not a common strategy among the Authors for the treatment of the disease, which can be surgical, radiotherapic or chemotherapic.

Diagnosis, Differential↗
PubMed2002

[Primary adenocarcinoma of the appendix. Case report and review of the literature].

A rare case of primary adenocarcinoma of the vermiform appendix (less than 250 cases described in the literature) in a 36 year-old female patient presenting signs and symptoms of an acute appendicitis is reported. Adeno-carcinoma of the vermiform appendix is a rare neoplasm of the gastrointestinal tract with an incidence of about 0,01-0,2%. Usually the diagnosis of adenocarcinoma of the vermiform appendix is difficult because symptoms and signs are not pathognomonic. In the case described, the diagnosis was intra and postoperative and confirmed by the pathological examination of the surgical specimens. At laparotomy, performed under suspicion of an acute appendicitis, disseminated disease was discovered, characterized by the involvement of the two ovaries, the left colon, the cecum, the vermiform appendix, with a peritoneal carcinosis and a hydroureteronephrosis. According to the dissemination of the disease, the surgical treatment was right hemicolectomy, anterior resection of left colon, bilateral oophorectomy and omentectomy. The post-operative course was regular. Adjuvant therapy was performed for 6 cycles, with 5FU and oxaliplatinum. The patient is still alive after 6 months and there is no sign of progression of the disease. A mild left hydroureteronephrosis is persistent.

Adenocarcinoma↗
PubMed2001

Cell cycle checkpoint efficiency and cellular response to paclitaxel in prostate cancer cells.

BACKGROUND: Defects in the cell cycle machinery of prostate cancer cells might impair the efficiency of cell cycle checkpoints and affect the cell response to chemotherapeutic drugs. We examined the relationship between the status of microtubule damage-activated checkpoints and the response of hormone-refractory prostate cancer cells to paclitaxel. METHODS: The two cell lines DU145 and PC3 harboring defects at proteins involved in the regulation of checkpoints activated by microtubule damage were examined for cell sensitivity, apoptotic response, and efficiency of checkpoints in response to paclitaxel. RESULTS: In spite of a comparable sensitivity to the antiproliferative effects of paclitaxel, DU145 and PC3 cells exhibited different cell cycle control at checkpoints activated by microtubule damage. A transient mitotic arrest was induced by the taxane in both cell lines. However, PC3 cells underwent a rapid mitotic slippage and displayed a defective postmitotic checkpoint as evidenced by the appearance of polyploid cells. In this cell line, paclitaxel-induced cell death was a slow and delayed event, occurring also after S-phase re-entry. The mitotic checkpoint appeared to be more stringent in DU145 cells compared to PC3 cells. Moreover, despite the expression of mutated proteins involved in the prevention of DNA endoreduplication (p53, pRb, and p16(INK4A)), these cells did not progress into the cell cycle but efficiently underwent apoptosis by 24 hr. Such a response of DU145 cells was associated with phosphorylation of the p21(WAF1) protein. CONCLUSIONS: These observations evidence that activation of checkpoints following microtubule damage in prostate cancer may be regulated through complex mechanisms possibly involving p21(WAF1). Our findings support that the status of cell cycle checkpoints might affect the modality of cell death. However, the relevance of the mode of cell death for the sensitivity to taxanes remains to be determined.

Antineoplastic Agents, Phytogenic↗
PubMed2001

Properties of the Escherichia coli rhodanese-like protein SseA: contribution of the active-site residue Ser240 to sulfur donor recognition.

The product of Escherichia coli sseA gene (SseA) was the subject of the present investigation aimed to provide a tool for functional classification of the bacterial proteins of the rhodanese family. E. coli SseA contains the motif CGSGVTA around the catalytic cysteine (Cys238). In eukaryotic sulfurtransferases this motif discriminates for 3-mercaptopyruvate:cyanide sulfurtransferase over thiosulfate:cyanide sulfurtransferases (rhodanese). The biochemical characterization of E. coli SseA allowed the identification of the first prokaryotic protein with a preference for 3-mercaptopyruvate as donor substrate. Replacement of Ser240 with Ala showed that the presence of a hydrophobic residue did not affect the binding of 3-mercaptopyruvate, but strongly prevented thiosulfate binding. On the contrary, substitution of Ser240 with an ionizable residue (Lys) increased the affinity for thiosulfate.

Amino Acid Motifs↗
PubMed2001

A role for loss of p53 function in sensitivity of ovarian carcinoma cells to taxanes.

Loss of p53 function has been linked to increased responsiveness to taxane treatment of ovarian carcinoma in clinical studies. We recently reported that the acquisition of cisplatin resistance in an ovarian carcinoma cell line (IGROV-1) was associated with mutation of p53 and collateral sensitivity to paclitaxel. The increased sensitivity to paclitaxel of the cisplatin-resistant subline appeared to be pharmacologically relevant since it was reflected in an in vivo sensitization to taxanes. To investigate the cellular and molecular basis of this phenomenon, we performed a comparative study of cellular response to taxanes (paclitaxel and the novel analog IDN 5109) in the parental cell line, containing wild-type p53 and its cisplatin-resistant p53 mutant subline (IGROV-1/Pt1). IDN 5109 was included in this study because of its higher potency and efficacy compared with paclitaxel on both tumor systems. The pattern of cellular response of the two ovarian cell lines was different. In IGROV-1 cells, apoptosis was an early event consequent to a transient mitotic arrest. The cell death of IGROV-1/Pt1 cells was a somewhat slow and delayed event, following mitotic arrest and appearance of hyperploid cells. The increased cytotoxic effect of IDN 5109, compared with paclitaxel, was associated with more marked p34(cdc2) dephosphorylation in IGROV-1 cells and higher Bcl-2 phosphorylation in IGROV-1/Pt1 cells after 24 hr of treatment. In each cell line, these biochemical events were not correlated with parallel levels of mitotic cells. Attempts to reintroduce wild-type p53 in IGROV-1/Pt1 were unsuccessful. However, in other p53-deficient cells (osteosarcoma SAOS), taxane treatment was associated with hyperploid progression and the introduction of wild-type p53 resulted in a reduced sensivity. Although our approach does not allow definitive conclusions, these results suggest that loss of p53-dependent post-mitotic checkpoint results in a different time-course of taxane-induced cell death following DNA reduplication. These events, more evident after exposure to the potent analog IDN 5109, support the notion that the enhanced sensitivity of p53 mutant cells is closely related to the different mode of cell death.

Antineoplastic Agents, Phytogenic↗
PubMed2000

Clavilactones, a novel class of tyrosine kinase inhibitors of fungal origin.

Targeting of deregulated protein tyrosine kinases has been proposed as a new approach in the therapeutic intervention against pathological processes including proliferative disorders and cancer. Using a screening approach based on a comparative evaluation of antiproliferative effects in a panel of tumor cells with differential expression of protein tyrosine kinases, three benzoquinoid macrolidic fungal metabolites produced by Clitocybe clavipes, clavilactones A, B, and D (CA, CB, and CD) and two semisynthetic derivatives of these products, diacetyl-CA and dimethyl-CA, were identified as inhibitors of protein tyrosine kinases. Naturally occurring CA, CB, and CD showed inhibitory activity in kinase assays against the Ret/ptc1 and epidermal growth factor receptor (EGF-R) tyrosine kinases, while being less effective against the v-Abl tyrosine kinase and p34(cdc2) serine/threonine kinase (IC(50) 2.8, 5.5, 81.3, and 128 microM respectively, for the most potent compound CD). CB was shown to be a non-competitive inhibitor of EGF-R with respect to ATP or poly(Glu(6)Ala(3)Tyr). CD also preferentially inhibited the growth of A431 cells, which overexpress a constitutively active EGF-R, as opposed to IGROV-1 and SKOV-3 cells, which express low levels of the receptor. Further, EGF-R was shown to be a target for clavilactones in A431 cells, since EGF-induced receptor autophosphorylation was inhibited in the presence of CB, CD, and diacetyl-CA. Both CD and diacetyl-CA displayed weak activity when administered daily (i.p.) to mice bearing ascitic A431 tumor. These findings indicate that clavilactones represent the prototypes of a new structural class of tyrosine kinase inhibitors deserving further investigation.

Agaricales↗
PubMed2000

Adriamycin, 14-hydroxydaunomycin, a new antitumor antibiotic from S. peucetius var. caesius. Reprinted from Biotechnology and Bioengineering, Vol. XI, Issue 6, Pages 1101-1110 (1969).

Streptomyces peucetius var. caesius, obtained from S. peucetius, the daunomycin producing microorganism, by mutagenic treatment, differs from the parent culture by the color of the vegetative and aerial mycelia and by its antibiotic producing ability. S. peucetius var. caesius accumulates adriamycin in submerged and aerated culture on a medium containing glucose, brewer's yeast, and inorganic salts both in shake flasks and in stirred fermenters. Isolation of the product is performed by solvent extraction, chromatography on buffered cellulose columns, and crystallization as the hydrochloride. The new antitumor agent, adriamycin, is the 14-hydroxy derivative of daunomycin.

Antibiotics, Antineoplastic↗
PubMed2000

Inhibition of transforming activity of the ret/ptc1 oncoprotein by a 2-indolinone derivative.

ret-derived oncogenes are frequently and specifically expressed in thyroid tumors. In contrast to the ret receptor, ret oncoproteins are characterized by ligand-independent tyrosine-kinase activity and tyrosine phosphorylation. In this study, novel synthetic arylidene 2-indolinone compounds were evaluated as inhibitors of the ret/ptc1 tyrosine kinase. Four compounds inhibited ret/ptc1 activity in immunokinase assay (IC50 27-42 microM) including one (1,3-dihydro-5,6-dimethoxy-3-[(4-hydroxyphenyl) methylene)-2H-indol-2-one) (Cpd 1) that selectively inhibited the anchorage-independent growth of NIH3T3 transformants expressing the ret/ptc1 gene (NIH3T3ptc1 cells). Following exposure to Cpd 1, the transformed phenotype of NIH3T3ptc1 cells was reverted, within 24 hr, to a normal fibroblast-like morphology in adherent-cell culture. In these cells, the constitutive tyrosine phosphorylation of ret/ptc1, of the transducing adaptor protein shc and of a series of co-immunoprecipitated peptides became much reduced, as demonstrated by immunoprecipitation/Western-blot analyses. Data presented provide additional evidence that ret/ptc1 is directly implicated in malignant transformation, and demonstrate the ability of Cpd 1 to interfere in the signal transduction pathway constitutively activated by the ret/ptc1 oncoprotein. These results confirm the interest of the arylidene 2-indolinone class of tyrosine-kinase inhibitors as tools for the study of ret signaling and the control of cell proliferation in ret- and ret/ptcs-associated diseases.

Animals↗
PubMed1998

Decreased drug accumulation and increased tolerance to DNA damage in tumor cells with a low level of cisplatin resistance.

In an attempt to examine the cellular changes associated with cisplatin resistance, we selected a cisplatin-resistant (A43 1/Pt) human cervix squamous cell carcinoma cell line following continuous in vitro drug exposure. The resistant subline was characterized by a 2.5-fold degree of resistance. In particular, we investigated the expression of cellular defence systems and other cellular factors probably involved in dealing with cisplatin-induced DNA damage. Resistant cells exhibited decreased platinum accumulation and reduced levels of DNA-bound platinum and interstrand cross-link frequency after short-term drug exposure. Analysis of the effect of cisplatin on cell cycle progression revealed a cisplatin-induced G2M arrest in sensitive and resistant cells. Interestingly, a slowdown in S-phase transit was found in A431/Pt cells. A comparison of the ability of sensitive and resistant cells to repair drug-induced DNA damage suggested that resistant cells were able to tolerate higher levels of cisplatin-induced DNA damage than their parental counterparts. Analysis of the expression of proteins involved in DNA mismatch repair showed a decreased level of MSH2 in resistant cells. Since MSH2 seems to be involved in recognition of drug-induced DNA damage, this change may account for the increased tolerance to DNA damage observed in the resistant subline. In conclusion, the involvement of accumulation defects and the increased tolerance to cisplatin-induced DNA damage in these cisplatin-resistant cells support the notion that multiple changes contribute to confer a low level of cisplatin resistance.

Antineoplastic Agents↗
PubMed1998

Biosynthetic anthracyclines.

This review summarizes the structure, the occurrence and the available data concerning the bioactivity of biosynthetic anthracyclines. The anthracyclines represent an important family of natural products produced by microorganisms of Streptomyces and related genera and include clinically useful agents for the medical treatment of human cancer. Chemically, the anthracyclines are glycosides characterized by a quinone tetracyclic aglycone and one or more deoxysugar units, mostly belonging to the L-hexopyranoside series, comprising generally an aminosugar. The different compounds belonging to this family are structurally related as they share a common biosynthetic pathway. Although some statements concerning structure activity relationships and molecular requirements for activity can be made, published data are not adequate for the comparative evaluation of potential antitumor efficacy of biosynthetic anthracyclines. This family of natural products is therefore still open for pharmacological investigation.

Antibiotics, Antineoplastic↗