Tumor markers in urogynaecological tumors.

Cathepsin D in the malignant progression of neoplastic diseases

Recent studies suggest that aspartic proteinase Cathepsin D may be implicated in the process of tumor invasion and metastasis. In fact several in vitro observations showed that this proteinase may facilitate the spread of neoplastic cells through different mechanisms related to its proteolytic activity by acting at different levels of the metastatic cascade. Cathepsin D may promote tumor cell proliferation by acting as an autocrine mitogen through the activation of latent forms of growth factors or by interacting with growth factor receptors. The enzyme was also shown to be able to degrade in vitro extracellular matrix and to activate latent precursors forms of other proteinases involved in…

Cathepsin D, B and L circulating levels as prognostic markers of malignant progression

Growing evidence indicates that lysosomal Cathepsins D (CD), B (CB) and L (CL) may promote carcinogenesis and tumor progression. Therefore, we evaluated their potential value as biochemical parameters of malignant progression in patients with benign diseases which may undergo malignant transformation, such as liver cirrhosis (LC) and chronic pancreatitis (CHP) as well as in hepatocellular carcinoma (HCC) and pancreatic cancer (DPC). CD, CB and CL serum levels were determined by immunoenzymatic assays in LC, CHP, HCC or DPC patients and correlated with a number of biochemical and clinical parameters of these diseases. CD serum levels were increased in LC, CHP and HCC, but not in the DPC grou…

Weekly paclitaxel and Pegylated liposomal doxorubicin as first line treatment in metastatic breast cancer patients

Background: Paclitaxel-Doxorubicin combination chemotherapy is highly active in metastatic breast cancer patients (pts) but may be cardiotoxic in a small percentage of cases. PLD is a new formulation of Doxorubicin with significant reduced cardiac toxicity and for this reason PLD can be given safe in elderly patients with cardiac risk factors or in younger patients with prior exposure to anthracycline-containing regimens. The main side effect of PLD is Hand-Foot syndrome but when given in intervals not below 4 weeks and with a dose intensity not exceeding 10 mg/sqm per week, this side effects is clearly reduced. Methods: : We carried out a phase 2 study to verify the activity of P 70 mg/sm …

Hereditary common cancers: molecular and clinical genetics.

This review focuses on the functional role and structural features of the genes involved in common hereditary cancers. Most of these tumors are sporadic and the genetic alterations responsible for their genesis take place over several cell generations; nevertheless, 5 to 10% of the human tumors are hereditary, with a rapid development. Cancer susceptibility genes have been classified as "gatekeepers" (e.g. RB1, ki-ras) and "caretakers" (e.g. hMLH1 and hMSH2, BRCA1). The first step in identifying individuals at high risk of developing a specific inherited form of cancer, and who should therefore undergo genetic tests, is the detailed construction of family history (an accurate cancer family …

Cathepsin D activity levels in colorectal cancer: Correlation with cathepsin B and L and other biological and clinical parameters

Cathepsin D, B and L activity levels were determined in colorectal cancer and correlated with a number of biological and clinical parameters. Our studies have evidenced significant higher activity levels of these lysosomal enzymes in tumor cytosol compared to paired normal mucosa as well as an evident increase of tumor specific cathepsin D activity in Dukes' stage A tumors compared to later stages (B, C and D). Furthermore, significant higher cathepsin B and L activity levels were observed in Dukes' stage A compared to Dukes' stage D tumors while significant higher cathepsin B activity levels were observed in tumors ≤5 cm than in those >5 cm as well as in moderately differentiated tumors…

Cathepsin D: A possible biochemical marker for anthracycline cardiomyopathy

This study was carried out in an attempt to assess the pattern of cathepsin D variations induced by Doxorubicin (DXR) and to clarify the role possibly played by this endopeptidase in the onset of anthracyclines-induced cardiotoxicity. We evaluated the variations in both total and 'sedimentable' enzyme activity of cathepsin D in the heart of mice treated once a week for up to 8 weeks with DXR (4 mg/kg i.v.b.wt.) and sacrificed 12h, 3 and 6 days after 1, 4, 5 and 8 administrations. Our results show that significant but transitory changes in both total and sedimentable activity of cathepsin D occur after each administration and decline after prolonged treatments. These data do not suggest, but…

Effects of zoledronic acid on proteinase plasma levels in patients with bone metastases.

Background: The effects of the bisphosphonate derivative zoledronic acid (ZA) on the > circulating levels of matrix metalloproteinase-2 (MMP-2), matrix metallo-proteinases-9 > (MMP-9), cathepsin B (Cath B) and urokinase-type plasminogen activator (uPA) in > patients with bone metastasis (BMTS) and the possible correlation with the symptomatic > response induced by this drug in these patients were evaluated. Patients and Methods: > Proteinase levels were determined by enzyme-linked immunosorbent assay (ELISA) in the > plasma of 30 patients with painful bone metastases from breast or prostate cancer > undergoing multiple treatment with ZA (4 mg i.v., every 4 weeks). Healthy subjects > (HS) of…

Stefin A and cathepsin B and L circulating serum levels in patients with malignant or non-malignant liver diseases: A preliminary report

Experimental and clinical studies have recently shown a significant correlation between increased activity levels of lysosomal proteinases Cathepsin B, L in tumor tissues and malignant progression. On the basis of these findings we have undertaken some preliminary studies to evaluate the clinical impact of these enzymes and their intracellular inhibitor Stefin A in patients with malignant and non malignant liver diseases. The serum levels of Cathepsin B, L and Stefin A resulted significantly increased (mean 7 folds) in patients with liver diseases as compared to healthy subjects . these findings suggest that Cathepsin B, Cathepsin L, and Stefin A serum levels may be potentially useful as pr…

p53 mutations in L3-loop zinc-binding domain, DNA-ploidy, and S phase fraction are independent prognostic indicators in colorectal cancer: A prospective study with a five-year follow-up

p53 gene alterations are among the most common events observed in colorectal cancer,and are accompanied frequently by DNA aneuploidy and high proliferative activity. The prognostic significance of such mutations remains controversial. We prospectively evaluated the prognostic significance of p53 mutations, DNA-ploidy, and S phase fraction (SPF) in a consecutive series of 160 colorectal cancer patients (median follow-up 71 months). Tumor DNA was screened for p53 mutations by PCR/single-strand conformational polymorphism/sequencing. DNA-ploidy and SPF were assessed by DNA flow cytometry. p53 mutations were detected in 68 of 160 (42.5%) cases. In 56% (38 of 68) of these, p53 mutations were fou…

Ductal lavage: a valid method of risk assessment and of early diagnosis in breast cancer.

Short term intensive preoperative chemotherapy with high doses of epirubicin plus G-CSF rescue for locally advanced Stage III breast carcinoma.

Effects of amsacrine (m-AMSA), a new aminoacridine antitumor drug, on the rabbit heart.

There is emerging clinical evidence that amsacrine (m-AMSA) administration may be associated with cardiotoxic effects such as severe, even fatal, ventricular arrhythmias and impairment of the inotropic performance of the heart. Information on the cardiac effects of m-AMSA in animals is scanty. Studies on mice, dogs, and monkeys have not evidenced the cardiotoxicity of the compound. The data presented in this paper show that m-AMSA causes acute ECG alterations in normal rabbits and a dose-related negative inotropic effect on the isolated rabbit heart, suggesting that this species may be a useful model for the study of the cardiac actions of this antiblastic.

Prognostic significance of DNA ploidy, S-phase fraction, and tissue levels of aspartic, cysteine, and serine proteases in operable gastric carcinoma

A consecutive series of 63 untreated patients undergoing surgical resection for stage I-IV gastric adenocarcinomas (GCs) has been prospectively studied. Our purpose was to analyze the predictive relevance of DNA ploidy, S-phase fraction (SPF), and tissue levels of lysosomal proteinases cathepsin D (CD), cathepsin B (CB), cathepsin L (CL), and urokinase-type plasminogen activator (uPA) and that of the intracellular cysteine proteinase inhibitor stefin A on clinical outcome. All of the patients taking part in this study were followed up for a median of 73 months. DNA aneuploidy was present in 71% of the cases (45/63), whereas 9% of these (4/45) showed multiclonality. Both DNA ploidy and SPF w…

Vinorelbine plus cisplatinum for the treatment of stage IIIB and IV non small cell lung carcinoma

Thirty consecutive patients with stage IIIB-IV non small cell lung cancer were treated with a combination of cisplatin 80 mg/m2 on day 1 plus vinorelbine 25-30 mg/m2 on days 1, 8. This cycle was repeated every 3 weeks. The overall response rate was 46%, with 1 patient showing a complete response and 13 patients (43%) a partial response with a mean duration of 8.4+ months. Six patients had a stabilization and 10 progressed. The main toxicities were represented by myelosuppression and nausea/vomiting. Grade 3 leukopenia was seen in 33% of cases, grade 2 thrombocytopenia in 12%, and phlebitis in the injection vein in 16%. Mild constipation was also recorded. The combination of cisplatin plus v…

5-Fluorouracil plus interferon α-2a compared to 5-fluorouracil alone in the treatment of advanced colon carcinoma: A multicentric randomized study

Biochemical modulation is one of the most interesting fields in cancer chemotherapy. Interferon-alpha (IFNalpha) is a cytokine that is able to influence the pharmacodynamics of 5-fluorouracil (5FU) through a number of mechanisms. With the aim of confirming some data emerging from the literature, we initiated a multicentric randomized study comparing the combination of 5FU and IFNalpha-2a with 5FU alone in the treatment of advanced or metastatic colon cancer. A group of 205 colon cancer patients (104 in the 5FU arm and 101 in the 5FU + IFNapha-2a arm) were included in the final intention-to-treat analysis. Rectal cancers were not considered eligible. All patients had measurable disease, were…

Antimetastatic activity of adriamycin in combinations with proteinase inhibitors in mice

The antimetastatic activity of adriamycin in combination with proteinase inhibitors was investigated in mice bearing the metastatic tumors L1210 leukemia, Lewis lung carcinoma or M5076 sarcoma. Leupeptin, a cathepsin B inhibitor, when administered as a single agent was devoid of antimetastatic activity but some therapeutic activity was noted in mice with Lewis lung carcinoma when the agent was administered in combination with adriamysin. Pepstatin A, a cathepsin D inhibitor, had no effect as a single agent in mice with L1210 leukemia but displayed some antimetastatic activity in mice with Lewis lung carcinoma. In mice with M5076 sarcoma the combination of pepstatin A and adriamycin resulted…

Effects of E-64 (cysteine-proteinase inhibitor) and pepstatin (aspartyl-proteinase inhibitor) on metastasis formation in mice with mammary and ovarian tumors.

The effects of E-64 (Cathepsin B and L inhibitor) and Pepstatin A (Cathepsin D inhibitor) on spontaneous and experimental metastasis formation were investigated in mice with MCa mammary carcinoma, M5076 ovarian sarcoma and L1210 leukemia. Pepstatin induced a marked decrease in the number of spontaneous metastasis in MCa or M5076 tumor bearing mice. This phenomenon was also noted with E-64 but only in M5076 tumor bearing mice. On the other hand, both these agents were unable to prevent the formation of experimental metastasis in mice injected i.v. with L1210, MCa or M5076 tumor cells or with tumor cells in which Cathepsin B, L and D activities were inhibited by a 24 hour continuous exposure …