bryostatin-1 and rhizoxin

New drug discovery continues to follow the time-honored paths of screening and novel target identification combined with analogue development and serendipity. The agents selected here reflect these various approaches. They include drugs already showing significant antitumor activity, eg, anthrapyrazoles, temozolomide, camptothecin analogues, and taxotere, and updated information is provided on their development. Other drugs just entering or currently in phase I trials include rhizoxin, which seems capable of overcoming multidrug resistance; the novel bioreductive agent EO9 [corrected]; and bryostatin, a highly potent protein kinase C agonist. Sequence specificity could well prove to be an important factor in the development of DNA-interactive agents, and information is provided on the progress with distamycin mustard and the new cyclopropylpyrroloindole analogues carzelesin and adozelesin.

Topics: Antineoplastic Agents; Bryostatins; Camptothecin; Docetaxel; Humans; Lactones; Macrolides; Neoplasms; Paclitaxel; Taxoids

New drug discovery continues to follow the time-honored paths of screening and novel target identification combined with analogue development and serendipity. The agents selected here reflect these various approaches. They include drugs already showing significant antitumor activity, eg, anthrapyrazoles, temozolomide, camptothecin analogues, and taxotere, and updated information is provided on their development. Other drugs just entering or currently in phase I trials include rhizoxin, which seems capable of overcoming multidrug resistance; the novel bioreductive agent EO9 [corrected]; and bryostatin, a highly potent protein kinase C agonist. Sequence specificity could well prove to be an important factor in the development of DNA-interactive agents, and information is provided on the progress with distamycin mustard and the new cyclopropylpyrroloindole analogues carzelesin and adozelesin.

Topics: Antineoplastic Agents; Bryostatins; Camptothecin; Docetaxel; Humans; Lactones; Macrolides; Neoplasms; Paclitaxel; Taxoids

Alkylolides and alkenylolides of 198-254 Da such as hexadecan-16-olide and 9-hexadecen-16-olide were chemically synthesized in the present study as new macrocyclic lactones that are structurally different from widespread natural macrocyclic lactones including bryostatin (887 Da) and rhizoxin (613 Da), and were investigated for antitumor activity to Ehrlich ascites tumor cells by mitochondrial dehydroganase-based WST-1 assay and dye-exclusion assay. Of the alkylolides having 12, 15 or 16 carbon-atoms (D12:0, P15:0 or H16:0) and alkenylolides having 15 or 16 carbon-atoms with a double bond (P15:1 or H16:1), H16:0 was the most carcinostatic when administered at 37 degrees C for 20 h, with cell deformation and microvillus disappearance as detected by scanning electron microscopy. The carcinostatic activity was increased markedly for H16:0 and P15:0 when the administration period was prolonged to 72 h, but was not enhanced by intramolecular introduction of a double bond for P15:1 or H16:1. Hyperthermia at 42 degrees C for 30 min additively intensified the carcinostatic activity for H16:0 and P15:0, but scarcely for D12:0, and intensified the alkenyloides P15:1 and H16:1 only upon the subsequent 72-h treatment. Invasion of human fibrosarcoma HT-1080 cells through the reconstituted basement membrane was inhibited by alkyl- and alkenylolides even after the short-term exposure at 25 microM for 3 h without diminishing the cell viability. H16:0 also exhibited the most inhibitory activity to tumor invasion in addition to the highest carcinostatic activity. Both inhibitions were promoted by combination with hyperthermia. Thus diverse alkyl-/alkenylolides, may be potent multi-applicable anticancer agents in terms of either dual inhibitory activities against both tumor progression and invasion or hyperthermia-combined therapy.

Topics: Animals; Antineoplastic Agents; Bryostatins; Carcinoma, Ehrlich Tumor; Cell Survival; Combined Modality Therapy; Fibrosarcoma; Humans; Hyperthermia, Induced; Lactones; Macrolides; Neoplasm Invasiveness; Tumor Cells, Cultured

The pharmaceutical formulation of a new anti-tumour agent has often been perceived as the bottleneck in anti-cancer drug development. In order to increase the speed of this essential development step, the Cancer Research Campaign (CRC), the European Organization for Research and Treatment of Cancer (EORTC) and the National Cancer Institute (NCI) agreed in 1987 to form the Joint Formulation Working Party (JFWP). The main goal of the JFWP is to facilitate the rapid progress of a new drug through pharmaceutical developmental to preclinical toxicology and subsequently to phase I clinical trial. Under the auspices of the JFWP around 50 new agents have been developed or are currently in development. In this report we present our formulation experiences since the establishment of the JFWP with a selected number of agents: aphidicolin glycinate, bryostatin 1, carmethizole, carzelesin, combretastatin A4, dabis maleate, disulphonated aluminium phthalocyanine, E.O.9, 4-hydroxyanisole, pancratistatin, rhizoxin, Springer pro-drug, SRI 62-834, temozolomide, trimelamol and V489. The approaches used and problems presented may be of general interest to scientists in related fields and those considering submitting agents for development.

Topics: Amaryllidaceae Alkaloids; Antineoplastic Agents; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Bryostatins; Chemistry, Pharmaceutical; Drug Stability; Excipients; Imidazoles; Isoquinolines; Lactones; Macrolides; Quaternary Ammonium Compounds; Solubility; Triazines