Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0598934 (tumor growth)
 58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Swainsonine, an indolizidine alkaloid, was initially used in biomedical research as a tool to investigate the biosynthesis and function of asparagine-linked 'complex' type oligosaccharide moieties of glycoproteins. Recently, swainsonine has generated interest in its potential use as an anticancer agent with reports that it (i) inhibits tumor growth and metastasis, (ii) augments natural killer (NK) and macrophage-mediated tumor cell killing, and (iii) stimulates bone marrow cell proliferation. The antineoplastic activity of swainsonine can be explained at least in part by augmentation of immune effector mechanisms. The potential application of swainsonine as an anticancer agent is discussed.
 ...
PMID:The potential importance of swainsonine in therapy for cancers and immunology. 175 3

Swainsonine, an indolizidine alkaloid, can decrease the organ colonization potential of metastatic murine tumor cells by augmentation of host immune effector mechanisms. In this report the above findings were extended by the demonstration that systemic administration of swainsonine strongly suppressed the growth of human breast carcinoma subcutaneous xenografts and experimentally induced lung metastases. This inhibition was not due to a direct effect of swainsonine on cell growth. However swainsonine treatment of tumor cells resulted in enhanced expression of HLA Class I antigens, and HLA class I mRNA. Swainsonine was a potent immunodulator as evidenced by the increased (a) cytotoxicity of splenocytes and macrophages, and, (b) proliferative potential of splenocytes and bone marrow cells. These data suggest that swainsonine-induced inhibition of tumor growth and metastases may be mediated via activation of host effector cells and/or alteration of tumor cell antigenicity.
 ...
PMID:Inhibition of growth of subcutaneous xenografts and metastasis of human breast carcinoma by swainsonine: modulation of tumor cell HLA class I antigens and host immune effector mechanisms. 212 82

Swainsonine, a plant alkaloid and potent inhibitor of Asn-linked oligosaccharide processing, has previously been shown to inhibit organ colonization by metastatic murine tumor cells and to inhibit the growth of transformed fibroblasts in soft agar. In this report, we show that swainsonine has antiproliferative activity against human tumor cells growing in tissue culture and as tumor xenografts in nude mice. The antiproliferative activity of swainsonine was additive with that of human interferon-alpha 2 (HuIFN-alpha 2) in cultures of HT29 colon carcinoma, SN12 renal carcinoma, and A375 melanoma cells. In vivo, the growth rate of HT29m human colon carcinoma tumors in athymic nude mice was reduced by supplementing their drinking water with swainsonine (49%) or by administering HuIFN-alpha 2 systemically (53%); combining these treatments reduced tumor growth by 78%. Combining swainsonine and HuIFN-alpha 2 treatments enhanced the activity of the interferon-inducible enzyme 2',5'-oligoadenylate [2',5'-oligo(A)] synthetase in HT29m tumors compared to that observed in tumors from mice treated with interferon alone. In vitro, swainsonine enhanced interferon-dependent induction of 2',5'-oligo(A) synthetase activity in low-density cultures of HT29m cells. However, swainsonine alone did not stimulate 2',5'-oligo(A) synthetase activity in vivo or in vitro, indicating that the antiproliferative effect of swainsonine is independent of interferon production. The results suggest that in addition to the previously reported antimetastatic activity of swainsonine, the plant alkaloid has antiproliferative activity that is independent from, but additive with, that of interferon in vivo and in vitro.
 ...
PMID:Inhibition of human HT29 colon carcinoma growth in vitro and in vivo by swainsonine and human interferon-alpha 2. 249 93

Swainsonine, an indolizidine alkaloid and competitive inhibitor of Golgi alpha-mannosidase II (EC 3.2.1.114), reduces tumor growth and stimulates immune function in mice. On the basis of these observations, a phase I clinical trial was initiated to determine whether swainsonine could be administered safely to cancer patients. We describe a method for extraction, acetylation, and quantification of swainsonine in human serum samples. Methyl alpha-D-mannopyranoside and methyl beta-D-galactopyranoside were added to serum samples as internal standards and, after sequential extraction of lipids and proteins with chloroform and acetonitrile, respectively, samples were acetylated with acetic anhydride and 4-dimethylaminopyridine and separated by gas-liquid chromatography. The identity of swainsonine and the internal standards after their extraction from serum and acetylation was confirmed by gas chromatography/mass spectrometry. Swainsonine was recovered at an efficiency of 90%, relative to internal standards, and calibration graphs were rectilinear from 3 to 18 mg/L with a detection limit of approximately 0.1 mg/L. The CV for multiple samples was < or = 6.7%. In patients receiving swainsonine (50-550 micrograms/kg per day) continuously for 5 days by intravenous infusion, serum concentrations of the drug reached 3-11.8 mg/L, 100 to 400 times greater than the 50% inhibitory concentration for Golgi alpha-mannosidase II and lysosomal alpha-mannosidases. Accurate measurements of swainsonine in biological fluids with this method should facilitate further clinical studies with the drug.
 ...
PMID:Measuring swainsonine in serum of cancer patients: phase I clinical trial. 813 Dec 79

Swainsonine, an alpha-mannosidase inhibitor which blocks Golgi oligosaccharide processing, represents a new class of compounds that inhibit both rate of tumor growth, and metastasis, in murine experimental tumor models. In this first phase I study, the quantitative and qualitative toxicities of swainsonine have been studied in patients given a continuous i.v. infusion over 5 days, repeated at 28-day intervals. Dose levels were escalated in increments of 100 micrograms/kg/day from 50-550 micrograms/kg/day. Nineteen patients with both solid tumor and hematological malignancies were given a total of 31 courses. Hepatotoxicity, particularly in patients with liver metastases, was the dose-limiting toxicity. The maximum tolerated dose (MTD) and the recommended starting dose (MTD -1 level) were 550 and 450 micrograms/kg/day, respectively. Common side effects included edema, mild liver dysfunction, a rise in serum amylase, and decreased serum retinol. Acute respiratory distress syndrome possibly precipitated by swainsonine resulted in a treatment-related death in a patient with significant pretreatment hepatic dysfunction. One patient with head and neck cancer showed > 50% shrinkage of tumor mass for 6 weeks after treatment. Two patients with lymphangitis carcinomatosis on chest X-ray noted improvement in cough and shortness of breath during the infusion of swainsonine and for 1 week thereafter. Clearance and serum half-life for swainsonine were determined to be approximately 2 ml/h/kg, and 0.5 day, respectively. Golgi oligosaccharide processing, a putative anticancer target for swainsonine was inhibited in peripheral blood lymphocytes as evidenced by a marked decrease in leukoagglutinin binding after 5 days of treatment. Oligomannosides in patient urine increased 5-to 10-fold over the 5 days of treatment, indicating that tissue lysosomal alpha-mannosidases were also blocked by swainsonine. Urine oligomannoside accumulation reached steady state at 3 days, approximately 1 day after serum drug levels reached steady state. The fraction of HLA-DR-positive cells in peripheral blood lymphocytes increased following 5 days of swainsonine treatment, an effect similar to that observed for peripheral blood lymphocytes from normal subjects cultured with swainsonine. No significant changes in CD3, CD4, CD8, CD16, and CD25 were observed. Swainsonine produces minimal toxicity when administered i.v. to cancer patients at dosages that inhibit both Golgi alpha-mannosidase II and lysosomal alpha-mannosidases. Detection of hepatic metastases or liver enzyme abnormalities prior to treatment predict for more significant toxicity.
 ...
PMID:A phase I study of swainsonine in patients with advanced malignancies. 813 47