Affiliations of authors: S. Waxman, Y. Jing, Mount Sinai School of Medicine, New York, NY; Z. Chen, G.-Q. Chen, Shanghai Institute of Hematology, China.
Correspondence to: Samuel Waxman, M.D., Mount Sinai School of Medicine, Box 1178, 100th and 5th Ave., New York, NY 10029.
We agree with the opinion of Huff et al. (1) that "the use of arsenicals must be tempered by toxicologic realities." Arsenic has been ranked highest in priority on a list of the top 20 hazardous substances by the Agency for Toxic Substances and Disease Registry and the U.S. Environmental Protection Agency (2). Indeed, cancers in many organs have been reported in populations living near smelters and drinking water with a contaminant of arsenic. However, arsenic alone has not been proven to induce cancer in an animal model (1). This fact implies either that humans are more sensitive to arsenic-induced cancer or to long-term exposure or that higher doses of arsenic are needed for carcinogenesis. Many proposed models of arsenic carcinogenesis tend to support a threshold relationship (2). Therefore, the medical use of arsenic under the threshold would be without higher risk for carcinogenesis.
Arsenic has been used for centuries for different medical purposes. Since 1865, Fowler's solution (potassium arsenite) has been used for the treatment of chronic myelocytic leukemia and continued to be an important agent until the discovery of busulfan and radiation therapy. Although case reports have suggested that prolonged use of arsenites may be associated with cancers at internal sites, large cohort studies showed no increase of internal cancers in the patients treated with Fowler's solution (3).
Several groups have confirmed the predictable induction of remission without severe toxicity by arsenic trioxide (As2O3) in a large series of patients with relapsed acute promyelocytic leukemia (APL). However, one group (4) reported severe toxicity in a few patients with APL. We (5) also observed unexpected severe liver toxicity in two newly diagnosed patients with APL after treatment with As2O3. Until now, secondary cancers have not been reported in patients with APL after treatment with As2O3. The low dose of As2O3, the method of administration (intravenous), or the duration of treatment may not have reached the threshold to induce secondary cancers. Moreover, recent pharmacokinetic studies (6) performed during and immediately after induction of remission showed that in vivo accumulation of As2O3 in peripheral tissues declined after withdrawal of the drug.
Whether As2O3 will be effective as a treatment for other forms of cancers including lymphoma is questionable. On the basis of recent mechanistic studies of As2O3-induced remission in APL (7), it seems that both differentiation and induction of apoptosis are involved in its therapeutic effect. As2O3 in vitro induces apoptosis in many tumor cell lines at clinically acceptable concentrations (1-2 µM). However, in vivo animal-tumor models are needed to evaluate its therapeutic effect because physiologic factors such as selenium may block As2O3-induced apoptosis (5). At the present time, As2O3 has been used in patients with relapsed APL and has proven to be a novel and effective therapy to prolong life. Our observation that As2O3 is not cross-resistant with doxorubicin (Adriamycin) and paclitaxel (Taxol) in P388/adr lymphoma with multidrug resistance supports a rationale to expand the use of this drug (5). If As2O3 is proven to be effective in patients with other types of cancers, like other cancer chemotherapeutic agents, then its use is justified despite potential carcinogenic risk.
EDITOR'S NOTE
Guido Kroemer and Hugues de Thé declined to respond to James Huff et al.'s correspondence.
REFERENCES
1
Huff J, Waalkes M, Nyska A, Chan P. Re: apoptosis and growth
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concentrations [letter]. J Natl Cancer Inst 1999;91:1690-1.
2 Goering PL, Aposhian HV, Mass MJ, Cebrian M, Beck BD, Waalkes MP. The enigma of arsenic carcinogenesis: role of metabolism. Toxicol Sci1999 ;49:5-14.[Abstract]
3 Cuzick J, Evans S, Gillman M, Price Evans DA. Medicinal arsenic and internal malignancies. Br J Cancer 1982;45:904-11.[Medline]
4 Huang SY, Chang CS, Tang JL, Tien HF, Kuo TL, Huang SF, et al. Acute and chronic arsenic poisoning associated with treatment of acute promyelocytic leukaemia. Br J Haematol 1998;103:1092-5.[Medline]
5 Jing Y, Dai J, Cahlmers-Redman RM, Tatton W, Waxman S. Arsenic trioxide selectively induces acute promyelocytic leukemia cell apoptosis via a hydrogen peroxide dependent pathway. Blood. In press 1999.
6
Shen ZX, Chen GQ, Ni JH, Li XS, Xiong SM, Qiu QY, et al. Use
of arsenic trioxide (As2O3) in the treatment of acute promyelocytic
leukemia (APL): II. Clinical efficacy and pharmacokinetics in relapsed patients. Blood 1997;89:3354-60.
7
Soignet SL, Maslak P, Wang ZG, Jhanwar S, Calleja E, Dardashti
LJ, et al. Complete remission after treatment of acute promyelocytic leukemia with arsenic
trioxide. N Engl J Med 1998;339:1341-8.
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