Carcinogenicity of 2',3'-dideoxycytidine in mice.
2',3'-dideoxycytidine (ddC) is a synthetic pyrimidine nucleoside analogue approved for treatment of HIV-positive patients. Previous studies indicated that ddC has the potential to cause thymic lymphoma in C57BL/6 x C3H F1 (hereafter called B6C3F1) mice. In this study, we evaluated the carcinogenic potential of ddC in two different mouse models. B6C3F1 hybrid mice carry ecotropic endogenous proviral sequences that may be activated to cause lymphoma, whereas NIH Swiss mice lack proviral sequences that can be expressed. The mice were treated with ddC by gavage at 500 and 1000 mg/kg/day for up to 6 months (human dose, 2.25 mg/day) and evaluated for toxicity, plasma levels of ddC, and pathological changes. Lymphocyte cell markers from the thymic lymphomas were assessed by immunophenotyping. Expression of p53 protein was evaluated using immunohistochemical staining. Treatment-related thymic lymphomas were present in both mouse models with a higher incidence in NIH Swiss than in B6C3F1 mice. The lymphomas were more prevalent in females than in males of both mouse models. Most mice with thymic lymphoma died during the course of the study. In addition to the thymus, lymphoma was often present in lymph nodes, spleen, and other organs. Lymphomas arose more frequently in mice that lack endogenous ecotropic retroviral sequences and thus were not due to activation of endogenous provirus. During the third month of the study, a few NIH Swiss mice that died had granulosa cell tumors of the ovary. Treatment-related but reversible thymic atrophy was observed in both mouse models. There was a very high correlation between the internal dose of ddC and the incidence of thymic lymphoma in both mouse models. Most of the lymphocytes from control thymuses and ddC-induced lymphomas were positive for Thy-1.2 (pan-T), heat stable antigen, and CD4 and CD8 markers, with no marked differences in the lymphocyte markers of the tumors between sexes or dose groups. p53 protein was detected in only 20% (23/115) of the ddC-induced lymphomas with mostly minimal expression in scattered cells. Because ddC induced lymphomas in two different mouse models, the potential carcinogenic risk should be considered in long-term treatment of HIV-positive patients, especially children and adolescent patients treated with ddC.
Rao
G N
GN
National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.
Collins
B J
BJ
Giles
H D
HD
Heath
J E
JE
Foley
J F
JF
May
R D
RD
Buckley
L A
LA
D000740:Anemia / Q000139:chemically induced; D000818:Animals; D019380:Anti-HIV Agents / Q000097:blood / Q000633:toxicity*; D001284:Atrophy / Q000139:chemically induced; D001835:Body Weight / Q000187:drug effects; D016516:CD4-CD8 Ratio; D015197:Carcinogenicity Tests; D005260:Female; D016399:Lymphoma, T-Cell / Q000097:blood / Q000139:chemically induced* / Q000737:chemistry / Q000473:pathology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D012737:Sex Factors; D013045:Species Specificity; D013950:Thymus Gland / Q000187:drug effects / Q000473:pathology; D013953:Thymus Neoplasms / Q000097:blood / Q000139:chemically induced / Q000737:chemistry / Q000473:pathology; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000032:analysis; D016047:Zalcitabine / Q000097:blood / Q000633:toxicity*
D019380:Anti-HIV Agents; D016159:Tumor Suppressor Protein p53; D016047:Zalcitabine