Preliminary clinical results with norgamem (thioproline) and revercan (2-amino-2-thiazoline): the first inducers of reverse transformation.

Abstract

Puck [6] defined the term reverse transformation as the recovery of normal morphology and normal membrane functions by transformed cells in tissue culture treated with high concentrations of dibutyryl adenosine 3’:5’-cyclic phosphate (cAMP). Gosalvez [3, 5] sought for compounds able to induce reverse transformation at pharmacologic concentrations using three screening systems; the capping of lymphocytes, the differentiation of the mold Dyctostelium discoideum, and the restoration of contact inhibition of HeLa cells in tissue culture. One compound, thiazoline-4-carboxylic acid, also called thioproline, passed the screening. This compound showed no toxicity in animals and no activity in transplantable animal tumors. It was brought to a phase I clinical trial in Spain in patients with advanced cancer of several types with encouraging results [1], especially in head and neck epidermoid carcinoma. The compound was called norgamem for use in clinical trails. Gosalvez [5] sought for analogs of thioproline, and only 2-amino-2-thiazoline passed the three screening systems. This compound, called revercan for clinical trials, was used in a clinical trial in Spain with bladder carcinoma and showed encouraging results [2]. Although norgamem and revercan could have activity in a wide series of tumors, we summarize here the current data on norgamem (epidermoid carcinoma of the head and neck) and on revercan (bladder carcinoma). Both compounds show antitumor activity without toxicity and, although the rate of response could not be defined due to excessive selection of patients and low number of patients, our results encourage the study of these two compounds in a wide phase II study of all tumor types. Whether norgamem and revercan will be demonstrated to be with or without utility in cancer clinics, they represent the first two inducers of reverse transformation or “transrec- ers,” a new group of substances in anticancer therapy which should be further explored.