mofarotene and Carcinoma--Non-Small-Cell-Lung

This phase I study was performed to assess the feasibility of combining cisplatin/etoposide (VP-16) with the arotinoid Ro 40-8757 and to determine the dose-limiting toxicity (DLT) of Ro 40-8757 in this combination. Patients with non-small cell lung cancer were eligible. Treatment consisted of Ro 40-8757 p.o. day 1-21, cisplatin 100 mg/m2 i.v. on day 2 and VP-16 100 mg/m2 i.v. on day 2-4, repeated every 3 weeks. Eighteen patients were evaluable for toxicity and response. The doses of Ro 40-8757 ranged from 84 mg/m2 once daily to 42 mg/m2 thrice daily (tid). DLT consisting of delayed nausea/vomiting was reached at 42 mg/m2 tid. Consequently, the maximum tolerated dose was set at one dose level below the DLT, i.e. 28 mg/m2 tid. Skin toxicity occurred but was well manageable. Pharmacological analyses showed a small increase in the volume of distribution of cisplatin and VP-16 between the first and third course. However, no relationship with side effects was found. A response was achieved in 50% of patients. The combination of cisplatin/VP-16 with Ro 40-8757 appears to be feasible at a dose schedule of 28 mg/m2 tid. The response rate was at the upper rate of what can be expected with cisplatin and VP-16.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cisplatin; Etoposide; Female; Humans; Lung Neoplasms; Male; Metabolic Clearance Rate; Middle Aged; Morpholines; Retinoids

A novel arotinoid with a morpholine structure in the polar end group Ro 40-8757 (4-[2-[p-[(E)-2(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2- naphthyl)propenyl]phenoxy]ethyl]-morpholine) was tested for its anti-proliferative activity against nine human cancer cell lines in vitro. The lines included two estrogen receptor positive breast cancer lines (MCF-7 and ZR-75-1), two estrogen receptor negative breast cancer lines (MDA-MB-231 and BT-20), one cervix carcinoma line (KB-3-1), two lung adenocarcinoma lines (A549 and HLC-1), one large cell lung cancer line (LXFL 529) and two colorectal lines (CXF 243 and CXF 280). Proliferation of all the lines, except the two lung adenocarcinoma lines, was inhibited by lower concentrations of Ro 40-8757 than those of all-trans retinoic acid (RA) or 13-cis RA giving the same level of inhibition. The degree of inhibition of RO 40-8757 was concentration and time dependent. The arotinoid was not cytotoxic and morphological signs by differentiation were not evident in cultures treated with Ro 40-8757 for up to 2 weeks. Because this compound is active on cells such as KB-3-1 that are not inhibited by all-trans RA and because it does not bind to nuclear retinoic acid receptors, it may represent a novel class of anti-proliferative agents.

Topics: Adenocarcinoma; Antineoplastic Agents; Breast Neoplasms; Carcinoma, Non-Small-Cell Lung; Cell Cycle; Cell Division; Cell Survival; Colorectal Neoplasms; Drug Screening Assays, Antitumor; Humans; Kinetics; Lung Neoplasms; Morpholines; Neoplasms; Receptors, Estrogen; Retinoids; Tetrazolium Salts; Thiazoles; Tretinoin; Tumor Cells, Cultured