For definition of Groups, see Preamble Evaluation.
Supplement 7: (1987) (p. 239)
CAS No.:
Chem. Abstr. Name: 4-[Bis(2-chloroethyl)amino]-L-phenylalanine
A. Evidence for carcinogenicity to humans (sufficient)
Epidemiological studies of patients with ovarian carcinoma [ref: 1-3], multiple myeloma [ref: 4,5] or breast cancer [ref: 6] have consistently shown very large excesses of acute nonlymphocytic leukaemia in the decade following therapy with melphalan. The relative risk was consistently estimated to be in excess of 100, to increase with increasing dose, and to be roughly the same with and without radiotherapy [ref: 7].
B. Evidence for carcinogenicity to animals (sufficient)
Melphalan has been tested in mice and rats by intraperitoneal injection, producing lymphosarcomas and a dose-related increase in the incidence of lung tumours in mice and peritoneal sarcomas in rats [ref: 8].
C. Other relevant data
Melphalan is a bifunctional alkylating agent. Patients treated therapeutically with melphalan had increased frequencies of chromosomal aberrations and sister chromatid exchanges in their peripheral lymphocytes [ref: 9].
Melphalan induced chromosomal aberrations in bone-marrow cells of rats treated in vivo. The compound induced chromosomal aberrations, sister chromatid exchanges and DNA damage in human cells in vitro. It induced transformation of C3H 10T1/2 cells. In cultured rodent cells, it induced chromosomal aberrations, sister chromatid exchanges, mutation and DNA damage. It induced aneuploidy and sex-linked recessive lethal mutations in Drosophila and mutation in bacteria [ref: 9].
Overall evaluation
Melphalan is carcinogenic to humans (Group 1).
For definition of the italicized terms, see Preamble Evaluation.
Also see previous evaluation: Vol. 9 (1975)
References
1. Einhorn, N., Eklund, G., Franzén, S., Lambert, B., Lindsten, J., & Söderhall, S. (1982) Late side effects of chemotherapy in ovarian carcinoma. A cytogenetic, hematologic, and statistical study. Cancer, 49, 2234-2241
2. Reimer, R.R., Hoover, R., Fraumeni, J.F., Jr & Young, R.C. (1977) Acute leukemia after alkylating-agent therapy of ovarian cancer. New Engl. J. Med., 297, 177-181
3. Greene, M.H., Boice, J.D., Jr, Greer, B.E., Blessing, J.A. & Dembo, A.J. (1982) Acute nonlymphocytic leukemia after therapy with alkylating agents for ovarian cancer. A study of five randomized clinical trials. New Engl. J. Med., 307, 1416-1421
4. Law, I.P. & Blom, J. (1977) Second malignancies in patients with multiple myeloma. Oncology, 34, 20-24
5. Gonzalez, F., Trujillo, J.M. & Alexanian, R. (1977) Acute leukemia in multiple myeloma. Ann. intern. Med., 86, 440-443
6. Greene, M.H., Harris, E.L., Gershenson, D.M., Malkasian, G.D., Jr, Melton, L.J., III, Dembo, A.J., Bennett, J.M., Moloney, W.C. & Boice, J.D., Jr (1986) Melphalan may be a more potent leukemogen than cyclophosphamide. Ann. intern. Med., 105, 360-367
7. Fisher, B., Rockette, H., Fisher, E.R., Wickerham, D.L., Redmond, C. & Brown, A. (1985) Leukemia in breast cancer patients following adjuvant chemotherapy or postoperative radiotherapy: the NSABP experience. J. clin. Oncol., 3, 1640-1658
8. IARC Monographs, 9, 167-180, 1975
9. IARC Monographs, Suppl. 6, 363-365, 1987
Synonyms
See Also:
Toxicological Abbreviations