AZT and Cancer

“The anti-HIV drug 3'-azido-3'-deoxythymidine (AZT) is used successfully for reduction of perinatal viral transmission. However toxic side effects including carcinogenesis are possible. To test this, pregnant CD-1 Swiss mice were given 25.0 or 12.5 mg AZT on gestation days 12-18… Findings for all remaining offspring [not killed for an earlier report] up to 2 years old are reported here. AZT effects were most prominent in female offspring, with a significant threefold increase in lung tumors, a reduction in lymphoblastic and follicle center cell lymphomas, and a significant increase in histiocytic sarcomas (0 in controls, 3% after low-dose AZT, and 8% after high-dose AZT, p = 0.022). Dose-dependent incidences of mammary gland, ovarian, and seminal vesicle tumors were low but significant: 0/106 controls, 3/105 low-dose, and 8/105 high-dose mice presented one of these neoplasms (p = 0.0025). Incidences of females showing any clearly AZT-related neoplasm, in lung, liver, ovary, or mammary gland or histiocytic sarcoma, in the second year, were 12/32 after the low dose and 14/27 after the high dose vs 3/23 controls (p = 0.0045). Also, the sensitivity of neonatal mice was assessed by administration of 25, 50, 100, or 200 mg/kg AZT on postnatal days 1 through 8. The effects at 2 years were similar to those seen after transplacental exposure, with significant increases in lung, liver, and mammary tumors in females…AZT had a much greater perinatal carcinogenic potency than it exhibited after administration to adult mice…the most worrisome new finding was the appearance, in the AZT exposure groups, of reproductive system tumors that were completely absent from untreated controls in this study, including mammary ademocarcinomas, ovarian tumors, seminal vesicle tumors, and testicular tumors.”

“727 infants with known ZDV [AZT] exposure prospectively followed from birth between 1989 through May/June 1996 were included…115 (61%) of ZDV recipients in PACTG 076 [a clinical trial giving AZT to mothers; 39% did not agree to continue with followup, a potential source of bias]…Also included…are 612 infants enrolled into the WITS study…Mean infant follow-up was longer for PACTG 076/219 participants at 38.3 months…[WITS participants had] a shorter mean follow-up of 14.5 months…The longest reported follow-up for infants was just over 6 years…In the cited rodent study, mice with in utero [in the womb] ZDV exposure…[had tumors] documented only in mice sacrificed at or after the human equivalent of the second decade [i.e. this study is worthless for determining whether there is a mid- to long-term risk of cancer from AZT exposure in the womb]”

“CD-1 mice exposed prenatally to 12.5 and 25.0 mg of AZT...had statistically significant increases in numbers of liver, lung and female reproductive tract tumors. These observations have been extended to offspring at 2 years of age...there was a 2- to 3-fold increase in the incidence (from 20% in controls to 55-60% in AZT groups) and multiplicities of lung tumors in AZT-exposed mice. The incidence of hepatocellular adenomas in the female mice exposed to prenatal AZT increase from 0 in the control group to 20% in the high dose AZT group, and hepatocellular carcinomas metastasizing to lungs were observed only in AZT-treated mice. Prenatal administration of AZT also increased the incidence of neoplasms of reproductive tract, female mammary gland epithelium and squamous cell epithelium of forestomach. AZT...significantly reduced the incidence of hematopoietic tumors”

“Perinatal treatment with 3'-azido-3'-deoxythymidine (AZT) has been found to reduce the rate of maternal-infant transmission of HIV; however, AZT is clastogenic at therapeutic doses in adult patients and induces cancers in the offspring of mice treated in utero. The purpose of the present study was to investigate the mutagenicity of AZT at the hypoxanthine-guanine phosphoribosyltransferase (hprt) locus of the human lymphoblastoid cell line, TK6, following in vitro exposures. ..There was a significant increase over background in hprt Mfs [mutation frequencies] in TK6 cells exposed to 300mM AZT for 3 days (1.8-fold increase). In cells exposed for 6 days, there was a decrease in...cell survival. ..These preliminary results indicate that AZT treatment is mutagenic and produces large deletions in human cells.”

“Similar levels of AZT-DNA incorporation were detected in peripheral blood from HIV-1-positive mothers and cord blood from their infants and tissues from newborn mice exposed to tumorigenic [cancer-causing] doses of AZT in utero. Therefore, the biologically effective dose (i.e. the amount of AZT that incorporated into DNA) was similar in both species even though the mouse daily dose of AZT was much higher than that received by humans.”

“At 1 year of age, the offspring of AZT-treated mice exhibited statistically significant, dose-dependent increases in tumor incidence and tumor multiplicity in the lungs, liver and female reproductive organs. AZT incorporation into nuclear and mitochondrial DNA was detected in multiple organs of transplacentally exposed mice and monkeys...AZT is genotoxic in fetal mice and monkeys and is a moderately strong transplacental carcinogen in mice examined at 1 year of age”

“…in adult mice, lifetime AZT administration induces vaginal tumors at a 10-20% incidence...In newborn monkeys and mice, AZT was incorporated into DNA of many fetal tissues...AZT appears to be a moderately-strong transplacental carcinogen [i.e. it crosses the placenta and may cause cancer in the fetus]”

“we have found positive correlations between the dose of AZT administered to female CD-1 mice, the incorporation of AZT into vaginal DNA, the hyperproliferation of the vaginal epithelial basal layer, and the aberrant expression of alpha-6 integrin toward the epithelial suprabasal strata of the vagina, a target organ for carcinogenesis in mice. These results suggest that there is an ordered progression of abnormal events leading to tumorigenesis in vaginal epithelial tissues.”

“after starting antiretroviral treatment...the estimated probability of developing lymphoma ...by 36 months, [was] 46.4% (CI, 19.6% to 75.5%)...a direct role of therapy itself cannot be totally discounted...Zidovudine [AZT] can act as a mutagen”