EXPRESSION OF DNA TOPOISOMERASE-I, DNA TOPOISOMERASE II-ALPHA, AND P53 IN METASTATIC MALIGNANT-MELANOMA

New anticancer drugs that target DNA topoisomerase I (topo I) are show ing activity against a wide variety of solid human neoplasms, These dr ugs work by a novel mechanism of action and cause topo I-mediated DNA breaks. These DNA breaks become lethal in cycling cells when they inte ract with the replication fork. Because of the challenges in treating metastatic malignant melanoma, we performed an immunohistochemical stu dy of this group of neoplasms to search for the presence of molecular markers that might indicate tumor response to topo I active drugs. Usi ng a new immunohistochemical stain for topo I, we found elevation of t his protein in 10 of 24 cases (41.6%) of metastatic malignant melanoma . The metastatic tumors that showed increased expression of topo I (2 or 3+) had statistically significant higher proliferation indices, me asured by immunohistochemical staining for DNA topo II-alpha, than did metastatic lesions with no detectable topo I expression. The average topo II-alpha index of metastatic melanomas with 2+ topo I expression was 45.1 (SD = 17.9) and with 3+ topo I expression was 52.3 (SD = 32.5 ). These values were found to be statistically different (P = .05) tha n the average topo II-alpha index of 18.9 (SD = 17.7) found for metast atic melanomas without detectable topo I immunostaining. Immunohistoch emical staining for p53 suggested abnormal p53 function in 6 of the 10 melanomas (60%), which showed elevations of topo I (2 to 3+ topo I im munostaining) but normal p53 function in all 14 metastatic lesions tha t showed normal topo I expression. Copyright (C) 1998 by W.B. Saunders Company.