taxane and Colonic-Neoplasms

Cancer chemotherapeutic treatment is a complex scientific task. The ChemoFx Drug Response Marker (DRM) assists physicians in identifying treatment protocols likely to be effective for specific patients.. The ChemoFx DRM was used to study drug response in vitro. Established human cancer cell lines and primary cultures of patient tumor specimens were challenged with chemotherapeutic agents to observe response of multiple tumor samples and determine whether drugs with similar mechanisms of action elicit similar response.. These studies demonstrated heterogeneous response among patient tumor samples and clustering of drug response with similar mechanisms of action. Also highlighted was the reproducibility of ChemoFx DRM and its utility in characterizing tumor response to chemotherapy.. Heterogeneous drug responses observed in vitro were similar to those observed clinically. Response characteristics were similar for drugs with similar mechanisms of action, suggesting response heterogeneity is determined at a cellular and molecular level.

Topics: Anthracyclines; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Cell Line, Tumor; Colonic Neoplasms; Drug Screening Assays, Antitumor; Female; Humans; Lung Neoplasms; Neoplasms; Ovarian Neoplasms; Platinum Compounds; Reproducibility of Results; Taxoids

Colorectal cancers are resistant to conventional chemotherapeutic treatments, including taxanes. gamma-Secretase is a multimeric membrane protein complex responsible for the intramembrane proteolysis of various type I transmembrane proteins, including amyloid beta-precursor protein and Notch. gamma-Secretase inhibitors have attracted increasing interest as anticancer drugs because of their ability to inhibit Notch signaling. However, the therapeutic usefulness of gamma-secretase inhibitors against colorectal cancers remains unclear.. The effects of gamma-secretase inhibitors on growth and apoptosis induced by various chemotherapeutic agents in colon cancer cells were evaluated using Hoechst 33342 staining, colony formation assay, and cell cycle analysis. The effect of gamma-secretase inhibitors on taxane-induced mitotic arrest was evaluated using the cyclin B1-associated histone H1 kinase assay and MPM-2 reactivity. The involvement of Notch signaling was evaluated by the silencing of Notch/CBF1 signaling by RNA interference.. gamma-Secretase inhibitors enhanced taxane-induced mitotic arrest and apoptosis of colon cancer cells both in vitro and in vivo, although gamma-secretase inhibitors alone did not affect growth and apoptosis of colon cancer cells. We also showed that this effect by gamma-secretase inhibitors was restricted to taxanes and colon cancer cells. Silencing of Notch/CBF1 signaling failed to affect paclitaxel-induced mitotic arrest and apoptosis.. These data suggest that gamma-secretase inhibitors could be a new therapeutic modality for overcoming resistance to taxanes in colorectal cancers.

Topics: Amyloid Precursor Protein Secretases; Antineoplastic Agents; Apoptosis; Bridged-Ring Compounds; Cell Culture Techniques; Cell Line, Tumor; Colonic Neoplasms; Enzyme Inhibitors; Humans; Mitosis; Taxoids; Vincristine

In the course of our investigation into the use of taxol as a lead compound to design new molecules with anti-cancer activity, we have synthesized four compounds based on protected guanosine coupled to taxol isoserine side-chain analogues. These analogues show in vitro anti-cancer activity against the colon cancer cell line SW480 that their constituent parts do not.

Topics: Antineoplastic Agents, Phytogenic; Bridged-Ring Compounds; Cell Line, Tumor; Colonic Neoplasms; Drug Design; Drug Screening Assays, Antitumor; Guanosine; Humans; Microtubules; Paclitaxel; Structure-Activity Relationship; Taxoids

Three new C-14 oxygenated taxane-type diterpenes, hongdoushans A-C (1-3), were isolated from the wood of Taxus yunnanensis together with four known diterpenes and two lignans. The absolute stereochemistry of the 2-methylbutyryloxy group attached at C-14 of the taxane skeleton was determined to be S by GC analysis of the methyl ester of 2-methylbutyric acid obtained after alkaline hydrolysis of 1 and 4 followed by treatment with CH(2)N(2). The complete stereostructure of the known compound 2alpha,5alpha,10beta-triacetoxy-14beta-[(S)-2-methylbutyryloxy]-4(20),11-taxadiene (4) was established for the first time. The isolates obtained were evaluated for their antiproliferative activity toward murine colon 26-L5 carcinoma and human HT-1080 fibrosarcoma cell lines.

Topics: Animals; Antineoplastic Agents, Phytogenic; Bridged-Ring Compounds; Cell Survival; Colonic Neoplasms; Diterpenes; Drug Screening Assays, Antitumor; Drugs, Chinese Herbal; Fibrosarcoma; Humans; Hydrolysis; Mice; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Paclitaxel; Plants, Medicinal; Stereoisomerism; Taxoids; Taxus; Trees; Tumor Cells, Cultured

We have compared the nature of interaction of certain taxanes with microtubular protein, and the mechanism of action underlying cytotoxic activity. Taxanes induced tubulin assembly in vitro, but only taxanes bearing side chain were capable of inducing the formation of stable tubulin polymers. Electron microscopy detections showed that taxane-induced polymers are structurally similar to microtubules formed by paclitaxel, with differences in length. Otherwise, light microscopy views have shown that intracellular microtubule network is deeply reorganized by taxanes into short fibers, unlike paclitaxel-bundled microtubules. Taxanes inhibited the growth of various human tumor cell lines, but cell cycle analysis did not always indicate a block in the G2/M phase. These agents alter some apoptotic signal transduction pathways, probably by a mechanism distinct from microtubule interaction. Briefly, the effectiveness of taxanes is closely related to their chemical structure, and depends on their interaction with microtubular protein. By virtue of this mechanism, some of these taxanes may provide usefulness for therapeutic improvements.

Topics: 3T3 Cells; Animals; Antibodies, Monoclonal; Antineoplastic Agents; Breast Neoplasms; Bridged-Ring Compounds; Cell Cycle; Cell Survival; Colonic Neoplasms; Female; G2 Phase; Humans; Mice; Microtubules; Mitosis; Structure-Activity Relationship; Taxoids; Tubulin; Tumor Cells, Cultured

Taxanes such as paclitaxel (Taxol) and docetaxel (Taxotere) are promising agents for use against ovarian cancer and other malignancies. Recently, SB-T-1011, a semisynthetic taxane, has been prepared from 14-hydroxy-10-deacetylbaccatin III. SB-T-1011 shows similar or greater in vitro cytostatic activity than paclitaxel, depending on the tumor cell line. The administration of taxanes is problematic due to their low solubility in most pharmaceutically acceptable solvents; formulations used clinically contain Cremophor/ethanol (diluent 12) or polysorbate 80/ethanol, excipients which may cause serious adverse effects. To eliminate these vehicles, we have prepared paclitaxel liposome formulations. The objective of the present work was to evaluate the antitumor activity of paclitaxel and two semisynthetic analogs in Cremophor-based and liposomal formulations. Antitumor activity was evaluated against A121a, a taxane-sensitive human ovarian tumor, growing as subcutaneous xenografts in athymic nude mice. Free and liposomal formulations of each taxane showed similar antitumor effect. The antitumor activity of paclitaxel and SB-T-1011 was similar, and docetaxel was more potent than either paclitaxel or SB-T-1011. Overall, taxane liposomes were better tolerated and more easily administered iv than taxane formulated in Cremophor/ethanol.

Topics: Animals; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Bridged-Ring Compounds; Carcinoma; Carcinoma, Non-Small-Cell Lung; Colonic Neoplasms; Docetaxel; Drug Carriers; Female; Humans; Liposomes; Lung Neoplasms; Mice; Mice, Nude; Neoplasm Transplantation; Ovarian Neoplasms; Paclitaxel; Taxoids