Zbigniew A. Cichacz

Isolation and structure of the cancer cell growth inhibitor dictyostatin 1

Dictyostatin 1 2, a new type of macrocyclic lactone bearing a 22-membered ring system, has been isolated (3.4 × 10–7% yield) from a Republic of Maldives marine sponge in the genus Spongia and found to strongly inhibit growth of the murine P388 lymphocytic leukaemia.

Immunosignaturing Can Detect Products from Molecular Markers in Brain Cancer

Immunosignaturing shows promise as a general approach to diagnosis. It has been shown to detect immunological signs of infection early during the course of disease and to distinguish Alzheimer’s disease from healthy controls. Here we test whether immunosignatures correspond to clinical classifications of disease using samples from people with brain tumors. Blood samples from patients undergoing craniotomies for therapeutically naïve brain tumors with diagnoses of astrocytoma (23 samples), Glioblastoma multiforme (22 samples), mixed oligodendroglioma/astrocytoma (16 samples), oligodendroglioma (18 samples), and 34 otherwise healthy controls were tested by immunosignature. Because samples were taken prior to adjuvant therapy, they are unlikely to be perturbed by non-cancer related affects. The immunosignaturing platform distinguished not only brain cancer from controls, but also pathologically important features about the tumor including type, grade, and the presence or absence of O6-methyl-guanine-DNA methyltransferase methylation promoter (MGMT), an important biomarker that predicts response to temozolomide in Glioblastoma multiformae patients.

Antineoplastic agents 293. The exceptional human cancer cell growth inhibitors spongistatins 6 and 7

Abstract A twenty year investigation of the South African marine sponge Spirastrella spinispirulifera (Carter, 1879) for antineoplastic constituents has now led to discovery of spongistatin 6 (1e) and 7 (2b) in 3.5 × 10−7% and 2.2 × 10−7% yields. Structural elucidations were based on detailed analyses of high field (400 and 500 MHz) 2D-NMR and high resolution mass spectra. Spongistatins 6 and 7 were exceptionally potent against a subset of human cancer cell lines in the NCI screening panel which are characteristically sensitive to cellular microtubule interactive antimitotics.

Immunosignature system for diagnosis of cancer

Significance Over much of the world, healthcare systems are facing an unprecedented challenge to meet the medical needs of an aging population while controlling costs. The early detection and treatment of diseases that are prevalent in older people is likely to be a key aspect of economically efficient, high-quality healthcare. In the case of cancer, the resection of a stage I or stage II tumor is often effectively a cure. An ideal diagnostic would allow early detection of disease on a single platform that could be used for any disease. Here, we demonstrate that the immunosignature diagnosis platform could potentially meet the universal platform requirement. Ongoing work will address the early detection requirement separately. Although the search for disease biomarkers continues, the clinical return has thus far been disappointing. The complexity of the body’s response to disease makes it difficult to represent this response with only a few biomarkers, particularly when many are present at low levels. An alternative to the typical reductionist biomarker paradigm is an assay we call an “immunosignature.” This approach leverages the response of antibodies to disease-related changes, as well as the inherent signal amplification associated with antigen-stimulated B-cell proliferation. To perform an immunosignature assay, the antibodies in diluted blood are incubated with a microarray of thousands of random sequence peptides. The pattern of binding to these peptides is the immunosignature. Because the peptide sequences are completely random, the assay is effectively disease-agnostic, potentially providing a comprehensive diagnostic on multiple diseases simultaneously. To explore the ability of an immunosignature to detect and identify multiple diseases simultaneously, 20 samples from each of five cancer cohorts collected from multiple sites and 20 noncancer samples (120 total) were used as a training set to develop a reference immunosignature. A blinded evaluation of 120 blinded samples covering the same diseases gave 95% classification accuracy. To investigate the breadth of the approach and test sensitivity to biological diversity further, immunosignatures of >1,500 historical samples comprising 14 different diseases were examined by training with 75% of the samples and testing the remaining 25%. The average accuracy was >98%. These results demonstrate the potential power of the immunosignature approach in the accurate, simultaneous classification of disease.

Antineoplastic agents. 536. New sources of naturally occurring cancer cell growth inhibitors from marine organisms, terrestrial plants, and microorganisms(1a,).

Bioassay-guided fractionation of extracts of various plants, marine organisms, and microorganisms has led to the discovery of new natural sources of a number of known compounds that have significant biological activity. The isolation of interesting and valuable cancer cell growth inhibitors including majusculamide C ( 1), axinastatin 5 ( 5), bengazoles A ( 6), B ( 7), and E ( 8), manzamine A ( 10), jaspamide ( 11), and neoechinulin A ( 19) has been summarized.

A broad-spectrum antifungal from the marine sponge Hyrtios erecta

Spongistatin 1, a macrocyclic lactone polyether from the marine sponge Hyrtios erecta, was fungicidal for a variety of opportunistic yeasts and filamentous fungi, including strains resistant to amphotericin B, ketoconazole and flucytosine. In broth macrodilution assays, MICs ranged from 0.195 to 12.5 microg/ml, and minimum fungicidal concentrations ranged from 3.12 to 25 microg/ml. Initial disk diffusion screens with six related macrocyclic lactone polyethers from H. erecta and Spirastrella spinispirulifera, revealed that these polyethers were also antifungal. The fungicidal activity of spongistatin 1 was confirmed in killing kinetics studies, where killing of Candida albicans and Cryptococcus neoformans occurred within 6 and 12 h, respectively. During the killing kinetics experiments, non-treated C. albicans maintained the yeast morphology. However, elongated forms resembling germ tubes were the predominant morphologic form in spongistatin 1-treated C. albicans cultures. The spongistatins show promise as potential antifungal agents and as probes to study fungal morphogenesis and nuclear division.

Isolation and structure of the remarkable human cancer cell growth inhibitors spongistatins 2 and 3 from an eastern indian ocean Spongia sp.

A black Spongia sp. In the Porifera class Demospongiae had been found to contain two new and exceptionally potent cell (human cancer) growth inhibitors named spongistatins 2 (1b) and 3 (1c)

Antineoplastic agents. 556. Isolation and structure of Coprinastatin 1 from Coprinus cinereus.

Cancer cell line bioassay-guided separation of an ethyl acetate extract prepared from a plant-associated fungus, Coprinus cinereus, led to the isolation of three new sesquiterpenes, coprinastatin 1 (1), coprinol (2), and the epimer (4a), of the known sesquiterpene triol (4b). The previously described sesquiterpene 3 and oxazolinone 5 were also isolated. The structure and relative configuration of coprinastatin 1 (1) were determined by HRMS and by 1D- and 2D-NMR spectroscopic analyses. The structure of terpene 2 was elucidated by single-crystal X-ray diffraction experiments. The remaining structures were similarly determined, structure 3 by spectroscopic analyses and both 4a and 5 by X-ray crystal structure determination. Coprinastatin 1 (1) was found to inhibit growth of the murine P388 lymphocytic leukemia cell line and the pathogenic bacterium Neisseria gonorrhoeae.

Antineoplastic agents 397: Isolation and structure of sesterstatins 4 and 5 from hyrtios erecta (the republic of maldives)

The wide ranging marine sponge Hyrtios erecta is the source of the spongistatins, a new class of macrocyclic lactone antineoplastic agents. Continuation of a detailed investigation of cancer cell growth inhibitory (P388 lymphocytic leukemia) fractions (trace) from H. erecta has revealed the presence (10(-5) to 10(-7)% yield) of cytotoxic pentacyclic sesterterpenes. Employing P388 leukemia and human tumor cell line-guided bioassay techniques, two new moderate inhibitors of cancer cells were isolated and named sesterstatins 4 (1a, P388 ED50 4.9 micrograms/mL) and 5 (1b, DU-145 prostate GI50 1.9 micrograms/mL). Similar to other sesterterpenes, sesterstatin 5 inhibited growth of a Gram-positive bacterium. High field (500 MHz) 2-D NMR techniques were primarily employed for initial structural assignments, and structural assignments were confirmed by X-ray crystal structure determination of sesterstatin 4 (1a) and 5 (1b).

Antineoplastic agents 315. Isolation and structure of the marine sponge cancer cell growth inhibitor phakellistatin 5

Abstract The Federated State of Micronesia (Chuuk) marine sponge Phakellia costada has been found to contain (9.6 x 10 −6 % yield) a new human cancer cell growth inhibitor designated phakellistatin 5 (3). Structural elucidation was accomplished employing high resolution FAB tandem MS/MS and high field (500 MHz) 2D-NMR techniques. Extension of the NMR experiments over the temperature range −25 to 25°C allowed the principal solution conformation of phakellistatin 5 to be assigned (Figure 2). The absolute configuration was found to correspond to S-amino acid units except for R-Asn.