Systemic treatment of neoplastic conditions with retinoids

Abstract

From the Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Taiwan. At the time of the conference (May 2-4, 1997), Dr. Hsu was Research Director of Oncology at Hoffmann-La Roche in Nutley, New Jersey. Reprint requests: Ming-Chu Hsu, PhD, Director, Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 128, Section II, Yen-Chiu-Yuan Road, Taipei 115, Taiwan, ROC. (J Am Acad Dermatol 1998;39:S108-13.) Copyright © 1998 by the American Academy of Dermatology, Inc. 0190-9622/98/$5.00 + 0 16/0/91616 Cancer is a multistage disease. Chromosome instability is a hallmark of cancer cells. From oncogene activation and tumor suppressor gene mutation to malignant and metastatic tumors, tumor cells continue to accumulate genetic lesions. Retinoids are the only class of drugs that have been tried in the clinic for chemoprevention and for chemotherapy of human malignancies. After the successful use of 13-cis retinoic acid (isotretinoin; Accutane) for the treatment of acne, several hyperplastic conditions of the skin (basal cell carcinoma, squamous cell carcinoma, cutaneous T-cell lymphoma, epidermodysplasia, keratoacanthoma, and actinic keratosis) were found to be responsive to retinoids.1,2 This led to the continuous exploration of retinoids by oncologists. Two main physiologic roles of retinoids are morphogenesis and cellular differentiation. An underlying cellular event that is known to be central to morphogenesis is programmed cell death (apoptosis). Cellular differentiation causes cells to exit from their cell cycle and to stop dividing.3 Derailment in the differentiation pathway and uncontrolled cellular proliferation have been known to be associated with malignant growth of tumors. More recently, in vitro and in vivo studies have pointed to a negative control of cell growth, apoptosis, to be yet another central player in the development of tumors.4 Abnormal proliferation of cells is normally counter-balanced by apoptosis. Progression of tumors eventually selects for cells deficient in their apoptosis pathways.5-7 Importantly, many chemotherapeutic agents used in the clinic have been shown to cause apoptosis in tumor cells.8,9 Therefore by virtue of their natural physiologic functions in cellular differentiation and apoptosis, retinoids would find their place in cancer prevention and therapy. The first encouraging clinical data were reported in 1988 by Huang et al10 at the Shanghai Second Medical College. Complete remission was found in 23 of 24 patients with acute promyelocytic leukemia (APL) treated with all-trans retinoic acid (Vesanoid). Morphologic differentiation of the leukemia cells could be seen a few days after initiation of drug treatment.11 Since that time, several thousand patients with APL worldwide have received the treatment. At the same time clinicians learned to manage leukocytosis (retinoic acid-APL syndrome) in some patients with dexamethasone or concurrent anthracycline chemo-therapy.12 In 1995 Vesanoid was registered to be the first differentiation therapy for cancer. Systemic treatment of neoplastic conditions with retinoids