ABSTRACT
Peritoneal metastasis (PM) in gastroenteropancreatic neuroendocrine tumors (GEP-NET) and hepato-pancreato-biliary (HPB) tumors has a low incidence and has rarely been studied as a stand-alone condition. The clinical relevance of PM in HPB tumors and GEP-NET arises from the fact that PM significantly worsens the prognosis of the underlying tumors. In GEP-NET, the particular situation is that PM has a negative prognostic impact compared to patients without metastases, which is not evident compared to patients with metastases in other locations. Complete surgical cytoreduction (CRS) is a curative treatment option for patients with PM in GEP-NET. Complete surgical resection should always be strived for, although patients may benefit from incomplete resection (70-90%) or resection of the primary tumor alone. Additional hyperthermic chemoperfusion (HIPEC) is currently not recommended. For nonresectable GEP-NET, systemic treatment is available that is oriented to the studies for generally metastasized GEP-NET. For PM in carcinomas of the bile duct and pancreatic carcinomas, there are no valid data or indications for CRS and HIPEC. In contrast, case series for PM in hepatocellular carcinoma (HCC) after CRS or CRS/HIPEC show good survival outcomes that justify a surgical approach under the condition of a complete resection. Patients with PM in GEP-NET and HCC should therefore be referred to a center for peritoneal tumor surgery to evaluate the option of complete CRS and use it as a curative option.
Subject(s)
Carcinoma, Hepatocellular , Hyperthermia, Induced , Liver Neoplasms , Neuroendocrine Tumors , Peritoneal Neoplasms , Humans , Peritoneal Neoplasms/surgery , Neuroendocrine Tumors/therapy , Carcinoma, Hepatocellular/therapy , Combined Modality Therapy , Liver Neoplasms/therapyABSTRACT
Seven novel ß-lactam antibiotics with activities against Gram-positive bacterial strains, among them methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci, were synthesized by amination of 2,5-dihydroxyphenylacetic acid in usable yields (30-60%). These products protected mice against an infection with S. aureus lethal to the control animals. The results show the usefulness of laccase for the synthesis of potential new antibiotics, in addition to the interdependence of the laccase substrates, the amino coupling partners, and the product formation, yield, and activity. The syntheses of ß-lactam antibiotics with 2,5-dihydroxyaromatic acid substructures (para-substituted) are then compared with those of 3,4-dihydroxyaromatic acid substructures (ortho-substituted). Para-substituted laccase substrates were better reaction partners in these syntheses than ortho-substituted compounds.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Biocatalysis , Laccase/metabolism , beta-Lactams/chemical synthesis , beta-Lactams/pharmacology , Amination , Animals , Bacteria/drug effects , Benzene/chemistry , Benzene/metabolism , Biotransformation , Female , Mice , Mice, Inbred BALB C , Sordariales/enzymologyABSTRACT
Novel cephalosporins, penicillins, and carbacephems were synthesized by amination of catechols with amino-beta-lactams like cefadroxil, amoxicillin, ampicillin and the structurally related carbacephem loracarbef using laccase from Trametes sp. All isolated monoaminated products inhibited the growth of several Gram positive bacterial strains in the agar diffusion assay, among them methicillin-resistant Staphylococcus aureus strains and vancomycin-resistant Enterococci. Observed differences in the cytotoxicity and in vivo activity in a "Staphylococcus-infected, immune suppressed mouse" model are discussed.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Catechols/chemistry , Laccase/metabolism , beta-Lactams/chemical synthesis , Amination , Anti-Bacterial Agents/pharmacology , Catalysis , Fungi/enzymology , Structure-Activity Relationship , beta-Lactams/pharmacologyABSTRACT
Sixteen novel cephalosporins were synthesized by amination of 2,5-dihydroxybenzoic acid derivatives with the aminocephalosporins cefadroxil, cefalexin, cefaclor, and the structurally related carbacephem loracarbef using laccases from Trametes sp. or Myceliophthora thermophila. All products inhibited the growth of several Gram positive bacterial strains in the agar diffusion assay, among them methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci. The products protected mice against an infection with Staphylococcus aureus lethal to the control animals. Cytotoxicity and acute toxicity of the new compounds were negligible. The results show the usefulness of laccase for the synthesis of potential new antibiotics. The biological activity of the new compounds stimulates intensified pharmacological tests.
Subject(s)
Cephalosporins/chemical synthesis , Fungi/enzymology , Gentisates/chemistry , Laccase/metabolism , Animals , Anti-Bacterial Agents/pharmacology , Bacteria/drug effects , Cyclophosphamide , Drug Resistance, Multiple, Bacterial , Female , Immunocompromised Host , Immunosuppressive Agents , Laccase/chemistry , Mice , Mice, Inbred BALB C , Staphylococcal Infections/drug therapyABSTRACT
Eight novel penicillins were synthesized by heteromolecular reaction of ampicillin or amoxicillin with 2,5-dihydroxybenzoic acid derivatives using a laccase from Trametes spec. All products inhibited the growth of several gram positive bacterial strains in the agar diffusion assay, among them methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococci. The products protected mice against an infection with Staphylococcus aureus lethal to the untreated animals. Cytotoxicity and acute toxicity of the new compounds were neglectable. The results show the usefulness of laccase for the synthesis of potential new antibiotics. The biological activity of the new compounds stimulates intensified pharmacological tests.
