David William End

Current status of clinical trials of farnesyltransferase inhibitors.

Farnesyltransferase inhibitors represent a new class of agents that target signal transduction pathways responsible for the proliferation and survival of diverse malignant cell types. Although these agents were developed to prevent a processing step necessary for membrane attachment and maturation of Ras proteins, recent studies suggest that farnesyltransferase inhibitors block the farnesylation of additional cellular polypeptides, thereby exerting antitumor effects independent of the presence of activating ras gene mutations. Clinical trials of two farnesyltransferase inhibitors–the tricyclic SCH66336 and the methylquinolone R115777–as single agents have demonstrated disease stabilization or objective responses in 10 to 15% of patients with refractory malignancies. Combinations of farnesyltransferase inhibitors with cytotoxic chemotherapies are yielding complete and partial responses in patients with advanced solid tumors. A phase I trial of R115777 in refractory and relapsed acute leukemias induced responses in 8 (32%) of 25 patients with acute myelogenous leukemia (including two complete remissions) and in two of three with chronic myelogenous leukemia in blast crisis. In patients with solid tumors, accessible normal tissues such as peripheral blood lymphocytes or, perhaps more germane to epithelial malignancies, buccal mucosa have provided surrogate tissues that allow confirmation that farnesyltransferase is inhibited in vivo at clinically achievable drug doses. In conjunction with the R115777 acute leukemia trial, serial measurements provided evidence of farnesyltransferase enzyme inhibition, interference with farnesyltransferase function (ie, protein processing), and blockade of signal transduction pathways in leukemic bone marrow cells. Preclinical studies of farnesyltransferase inhibitor resistance and clinical trials of farnesyltransferase inhibitors in combination with other agents currently are in progress.

Farnesyl Protein Transferase Inhibitors and Other Therapies Targeting the Ras Signal Transduction Pathway

The year 2000 will be a significant date for the field of Ras-related therapies since numerous agents will have Phase II clinical efficacy data maturing to provide proof of principle for this cancer treatment strategy. These data will also provide an important milestone for the cancer research community since these molecules represent a small vanguard of oncology drug discovery projects predicated on molecular targets. We can only hope that these agents are a successful harbinger for the formidable number of targeted therapies that will be entering development pipelines in the coming years.

Farnesyl Protein Transferase Inhibitor ZARNESTRA™ R115777 - History of a Discovery

R115777 (R)-6-amino[(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone is a potent and selective inhibitor of farnesyl protein transferase with significant antitumor effects in vivo subsequent to oral administration in mice. Taking its roots into Janssens ketoconazole and retinoic acid catabolism programs, our interest into Ras prenylation process led us stepwise to identify the key structural features of R115777. Methodology, structure activity relationships, and pharmacology will be presented. R115777 is currently in phase III clinical evaluation.

Experimental studies with liarozole (R 75,251): an antitumoral agent which inhibits retinoic acid breakdown.

Liarozole reduced tumor growth in the androgen-dependent Dunning-G and the androgen-independent Dunning MatLu rat prostate carcinoma models as well as in patients with metastatic prostate cancer who had relapsed after orchiectomy. In vitro, liarozole did not have cytostatic properties, as measured by cell proliferation in breast MCF-7 and prostate DU145 and LNCaP carcinoma cell lines. It did not alter the metabolism of labeled testosterone i.e. the 5 alpha-reductase in cultured rat prostatic cells. In mouse F9 teratocarcinoma cells liarozole did not show any retinoid-like properties but enhanced the plasminogen activator production induced by retinoic acid. Furthermore, liarozole and retinoic acid similarly reduced the growth of the androgen-dependent Dunning-G tumor in nude mice and inhibited tumor promotion elicited by phorbol ester in mouse skin. These data have raised the hypothesis that the antitumoral properties of liarozole may be related to inhibition of retinoic acid degradation, catalyzed by a P-450-dependent enzyme that is blocked by the drug.

A rapid assay for measuring the metabolism of [3H]-retinoic acid in cell cultures.

A simple method was developed to detect the metabolism of [3H]-retinoic acid to polar products using intact tumor cells in culture. Unaltered [3H]-retinoic acid was separated from more polar metabolites using C18-bonded solid phase extraction cartridges. Separation of unaltered retinoic acid and polar metabolites was confirmed by HPLC. The murine mammary carcinoma cell line TA3 Ha used in these studies converted 40% to 50% of added radioactive retinoic acid to polar metabolites released into the culture medium during a 4-hr incubation period. Metabolism of [3H]-retinoic acid by TA3 Ha cells was inhibited by the cytochrome P-450 inhibitors ketoconazole, clotrimazole, and liarozole. The simplicity and rapidity of this assay should make it useful for evaluating compounds as inhibitors of retinoic acid metabolism.

Interactions of Abiraterone, Eplerenone, and Prednisolone with Wild-Type and Mutant Androgen Receptor: A Rationale for Increasing Abiraterone Exposure or Combining with MDV3100—Letter

We read with interest the report from Richards and colleagues ([1][1]) on the potential interactions of abiraterone, eplerenone, and prednisolone with wild-type and mutant androgen receptor (AR). Abiraterone is a CYP17A1 inhibitor that blocks androgen biosynthesis in the testes, adrenals, and