Levels of active tyrosine kinase receptor determine the tumor response to Zalypsis.

Background: Zalypsis(®) is a marine compound in phase II clinical trials for multiple myeloma, cervical and endometrial cancer, and Ewing's sarcoma. However, the determinants of the response to Zalypsis are not well known. The identification of biomarkers for Zalypsis activity would also contribute to broaden the spectrum of tumors by selecting those patients more likely to respond to this therapy.

New interfacial microtubule inhibitors of marine origin, PM050489/PM060184, with potent antitumor activity and a distinct mechanism.

We have investigated the target and mechanism of action of a new family of cytotoxic small molecules of marine origin. PM050489 and its dechlorinated analogue PM060184 inhibit the growth of relevant cancer cell lines at subnanomolar concentrations. We found that they are highly potent microtubule inhibitors that impair mitosis with a distinct molecular mechanism.

Expression of XPG protein in human normal and tumor tissues.

XPG (Xeroderma pigmentosum group G complementing factor) is a protein associated with DNA repair and transcription. Point mutations in ERCC5, the gene coding for XPG, cause the cancer-prone disorder xeroderma pigmentosum (XP) while truncation mutations give rise to individuals with the combined clinical features of XP and Cockayne syndrome. Polymorphisms of ERCC5 or alterations in XPG mRNA expression were also associated to an increase risk of different cancers types and to prognosis of cancer patients.

Irvalec inserts into the plasma membrane causing rapid loss of integrity and necrotic cell death in tumor cells.

Irvalec is a marine-derived antitumor agent currently undergoing phase II clinical trials. In vitro, Irvalec induces a rapid loss of membrane integrity in tumor cells, accompanied of a significant Ca(2+) influx, perturbations of membrane conductivity, severe swelling and the formation of giant membranous vesicles. All these effects are not observed in Irvalec-resistant cells, or are significantly delayed by pretreating the cells with Zn(2+).

The role of p53 in the cellular toxicity by active trans-platinum complexes containing isopropylamine and hydroxymethylpyridine.

Despite some initial research that reported a lack of activity of trans geometry, complexes with general formula trans-[PtCl2(L)(L')] exhibit an important cytotoxic activity in cisplatin-sensitive and resistant cell lines. Based on the proposed mechanism of action for the trans-platinum compounds, they might form DNA adducts initiating a DNA-damage response and ultimately ending in the activation of the p53 protein. In the present work, we have studied the biochemical properties of the trans-[PtCl2(isopropylamine)(L)] complexes (where L is 3- or 4-(hydroxymethyl)-pyridine) against several cell lines and the relationship between cytotoxicity and the protein p53.

Using cells devoid of RAS proteins as tools for drug discovery.

Mutational activation of RAS proteins occurs in nearly 30% of all human tumors. To date direct pharmacological inhibition of RAS oncoproteins has not been possible. As a consequence, current strategies are focusing on the development of inhibitors that target those kinases acting downstream of RAS proteins, including those of the RAF/MEK/ERK and PI3K/AKT pathways.

Molecular pharmacology and antitumor activity of Zalypsis in several human cancer cell lines.

Zalypsis is a new synthetic alkaloid tetrahydroisoquinoline antibiotic that has a reactive carbinolamine group. This functionality can lead to the formation of a covalent bond with the amino group of selected guanines in the DNA double helix, both in the absence and in the presence of methylated cytosines. The resulting complex is additionally stabilized by the establishment of one or more hydrogen bonds with adjacent nucleotides in the opposite strand as well as by van der Waals interactions within the minor groove.

Influence of (hydroxymethyl)pyridine and pyridine-carboxylic acids, in trans-position to the isopropylamine and amine ligands, on the cytotoxicity of platinum complexes.

trans-Pt(II) Complexes with aliphatic amines and planar amines such as (hydroxymethyl)pyridines, and pyridine-3- and pyridine-4-carboxylic acids were synthesized and screened for their potential cytotoxic activity in different cancer cell lines used at the NCI for in vitro screens, i.e., MCF7, NCIH460, and SF268.

Levels of p27(kip1) determine Aplidin sensitivity.

Aplidin (plitidepsin) is a novel anticancer drug isolated from the marine tunicate Aplidium albicans. Aplidin shows potent antitumor activity in preclinical models against a wide variety of human tumors. Aplidin is currently in phase II clinical trials in a variety of solid tumors and hematologic malignancies.

Structure-activity relationship of new trans-platinum(II) and (IV) complexes with cyclohexylamine. Interference with cell cycle progression and induction of cell death.

The new trans-Pt complexes, derived from trans-[PtCl2(amine)(dimethylamine)] and trans-[PtCl2(OH)2(amine)(dimethylamine)], were synthesized and characterized studying the structure-activity relationship and testing their antiproliferative activity. Their evaluation as cytotoxic agents towards different cancer and normal cell lines is presented. These compounds are active in a panel of tumor cell lines at low micromolar range.

Extreme sensitivity to Yondelis (Trabectedin, ET-743) in low passaged sarcoma cell lines correlates with mutated p53.

Yondelis (Trabectedin, ET-743) is a marine anticancer agent currently in Phase II/III development in patients with advanced pretreated soft tissue sarcoma. In the present study, we generated a panel of low passaged tumor cell lines from samples explanted from chemonaive sarcoma patients with different tumor types. We assessed in vitro sensitivity/resistance to Trabectedin and doxorubicin in a panel of sarcoma cell lines and examined the correlation between molecular alterations in DNA repair genes and sensitivity to Trabectedin.

Inhibition of phosphatidylinositol-3-kinase synergizes with gemcitabine in low-passage tumor cell lines correlating with Bax translocation to the mitochondria.

Apoptotic pathways, including the phosphatidylinositol-3-kinase (PI3K)/AKT survival pathway, are altered in most cancer cells in relation to their normal counterparts and these differences may present an excellent therapeutic window. To gain insight into the relevance of the PI3K pathway as a target for drug discovery we generated tumor cell lines from different tumor samples that we maintained at low passage. The characterization of these cell lines indicates that all of them have constitutively activated the PI3K pathway through different mechanisms.

Transcriptional signature of Ecteinascidin 743 (Yondelis, Trabectedin) in human sarcoma cells explanted from chemo-naive patients.

Ecteinascidin 743 (ET-743; Yondelis, Trabectedin) is a marine anticancer agent that induces long-lasting objective remissions and tumor control in a subset of patients with pretreated/resistant soft-tissue sarcoma. Drug-induced tumor control is achievable in 22% of such patients, but there is no clear indication of the molecular features correlated with clinical sensitivity/resistance to ET-743. Nine low-passage, soft-tissue sarcoma cell lines, explanted from chemo-naive patients with different patterns of sensitivity, have been profiled with a cDNA microarray containing 6,700 cancer-related genes.

Cellular senescence induced by p53-ras cooperation is independent of p21waf1 in murine embryo fibroblasts.

Oncogenic activation in primary murine fibroblasts initiates a senescence-like cell cycle arrest that depends on the p53 tumor suppressor pathway. Conditional p53 activation efficiently induced a reversible cell cycle arrest but was unable to induce features of senescence. In contrast, coexpression of oncogenic ras with p53 produced an irreversible cell cycle arrest that displayed features of cellular senescence.

Overexpression of cyclin D1 inhibits TNF-induced growth arrest.

Although activated macrophages destroy cancer cells more effectively than normal cells, the facility to escape activated macrophages is a characteristic of tumor cells. One of the mechanisms responsible for the specific killing of tumor cells by macrophages is the production of the cytokine tumor necrosis factor alpha (TNF). Therefore, resistance to TNF may provide such cancer cells a selective advantage against host elimination.