Re: Apoptosis and growth inhibition in malignant lymphocytes after treatment with arsenic trioxide at clinically achievable concentrations.

Zhu et al. (1) indicated that “As2O3 may prove useful in the treatment of malignant lymphoproliferative disorders” in general, and Kroemer and de Thé (2) concluded with the statement that “irrespective of the molecular details, it appears that arsenic constitutes a welcome addition to the clinician’s armamentarium for the chemotherapy of leukemia.” Their major theme centers on the mechanism of arsenic trioxide in eradicating acute promyelocytic leukemia (APL). This is a major cancer chemotherapeutic advance if proven correct. However, we believe that the use of arsenicals must be tempered by toxicologic realities (3,4). In 1888, Hutchinson (5) described with utmost clarity the diagnosis and progression of arsenic-induced cancer in humans exposed for medicinal purposes: “I have two separate propositions to maintain, one of which is, however, of great importance to the other. The first is that by the prolonged internal use of arsenic the nutrition of the skin may be seriously affected, and that, amongst other changes, warty and corn-like indurations may be produced. The second goes much further and asserts that if the drug be continued these ‘arsenic corns’ may assume a tendency to grow downwards and pass into epithelial cancer.” The remainder of his remarkable article detailed case reports and correspondence surrounding the use of Fowler’s solution (1% potassium arsenite) for treating skin disorders and cancer as well as the associated arsenic-induced keratosis and secondary tumor formation. Arsenicals have been used widely as medicinals to treat various disorders, including arthritis, asthma, psoriasis, syphilis, and cancer; these long-standing pharmacologic uses have diminished because of toxicity, and arsenicals were frequently put to nefarious uses. Nonetheless, arsenicals are still used in agriculture and industry (4). Arsenic is a common contaminant of drinking water; thus, arsenic exposures are not uncommon. Occupational exposures to higher levels of arsenic occur, as do exposures of populations living near smelters. Cancers in humans associated with arsenic exposure include those of skin, lung, liver, gastrointestinal tract, hematopoietic system, kidney, and, possibly, urinary bladder and brain. Therefore, in arsenic, we have a potent carcinogen for a variety of organs via a variety of exposure routes. The fact that arsenicals, when given alone, have not been shown convincingly to induce tumors in laboratory animals may indicate that humans are more sensitive to arsenic-induced cancers, an alarming prospect. In this regard, arsenic trioxide has not been tested adequately for carcinogenicity in experimental animals (6). Whereas the use of arsenic trioxide in the chemotherapy of APL, and perhaps other hematopoietic cancers, has great clinical potential, arsenic and arsenic compounds are indeed carcinogenic to humans (3,4). Not that this adverse health effect should deter the use of arsenic trioxide to treat life-threatening diseases like APL, but all individuals involved should be fully aware of these long-known toxic and carcinogenic hazards. Indeed, a certain level of risk is accepted with the use of any drug, and the level of acceptable risk is justifiably higher in cancer chemotherapy because of the gravity of the diseases. However, like other paradoxical carcinogens, arsenic trioxide must be used with the realization and due caution that iatrogenic (i.e., treatment-induced), secondary tumors [and other toxic effects; (7)] may develop with long-term use.