Enhanced Cancer Growth in Mice Administered Daily Human-Equivalent Doses of Some H1-Antihistamines: Predictive In Vitro Correlates

Brandes, Lorne J.; Warrington, Robert C.; Arron, R. J.; Bogdanovic, R.Patricia; Fang, Wei; Queen, Gary; Stein, Douglas; Tong, Jiangang; Zaborniak, C. L. F.; LaBella, Frank S.

doi:10.1093/jnci/86.10.770

Cited by 45 publications

(38 citation statements)

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“…Other tricyclic analogues of amitriptyline, clomipramine and desipramine, exhibited the same properties (81,82). Also, several antihistamines enhanced melanoma and fibrosarcoma in mouse in vitro assays (83).…”

Section: Promoters and Protective Agentsmentioning

confidence: 87%

Nonhormonal drugs and cancer.

Stolley

Zahm

1995

Environ Health Perspect

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Nonhormonal drugs probably account for only a small proportion of human cancer but have contributed many valuable insights into carcinogenic mechanisms. The antineoplastics, radiopharmaceuticals, and a few other agents account for most of the known drug-induced cancer. A number of other agents are under suspicion, usually due to studies in laboratory animals or to preliminary clinical or epidemiologic observations. This group includes some drugs in widespread use such as clofibrate and cimetidine. For a few drugs that are carcinogenic in animals, such as dapsone and isoniazid, epidemiologic studies have shown little to no evidence of carcinogenicity. Recent experimental studies have shown tumor promotion by the commonly used antidepressants amitriptyline and fluoxetine and some antihistamines, which deserve epidemiologic investigation of cancer risk. Some drugs may also protect against cancer, as suggested by the lower risk of colorectal cancer among regular users of nonsteroidal antiinflammatory drugs. Pharmacoepidemiologic studies must take into account possible confounding by the original conditions for which drugs were taken and the typically long latency period of drug-induced cancer. Improved postmarketing surveillance, continued routine case-control surveillance, and ad hoc case-control and cohort studies are needed to evaluate drugs already in use as well as newly introduced agents. -Environ Health Perspect 103 (Suppl 8):191-196 (1995)

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Section: Promoters and Protective Agentsmentioning

confidence: 87%

Nonhormonal drugs and cancer.

Stolley

Zahm

1995

Environ Health Perspect

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“…Promethazine inhibits the effect of histamine on endotoxins against certain solid tumors (25). Another report suggests that certain H1 antagonists increase the growth rate of melanoma and fibrosarcoma cell lines (26). In any case it is now well documented by animal studies and clinical data that H1 receptor antagonists do not promote tumor formation (27).…”

Section: Discussionmentioning

confidence: 99%

Translationally controlled tumor protein is a target of tumor reversion

Tuynder

Fiucci

Prieur

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

217

219

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By analyzing the gene expression profile between tumor cells and revertant counterparts that have a suppressed malignant phenotype, we previously reported a significant down-regulation of translationally controlled tumor protein (TCTP) in the revertants. In the present study, we derived, by using the H1 parvovirus as a selective agent, revertants from three major solid cancers: colon, lung, and melanoma cell lines. These cells have a strongly suppressed malignant phenotype both in vitro and in vivo. The level of TCTP is decreased in most of the revertants. To verify whether inhibition of TCTP expression induces changes in the malignant phenotype, in the classical, well established model of ''flat reversion,'' v-src-transformed NIH3T3 cells were transfected with antisense TCTP. By inhibiting the expression of TCTP, the number of revertant cells was raised to 30%, instead of the reported rate for spontaneous flat revertants of 10 ؊6 . Because TCTP encodes for a histamine-releasing factor, we tested the hypothesis that inhibitors of the histaminic pathway could be effective against tumor cells. We show that some antihistaminic compounds (hydroxyzine and promethazine) and other pharmacological compounds with a related structure (including thioridazine and sertraline) kill tumor cells and significantly decrease the level of TCTP. All together, these data suggest that, with tumor reversion used as a working model, TCTP was identified as a target and drugs were selected that decrease its expression and kill tumor cells.

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“…No increased risk of breast cancer was evident with the use of these medications. Most notably, the use of astemizole (ORϭ1.08, 95% CI: 0.64, 1.82) or loratadine (ORϭ0.92, 95% CI: 0.74, 1.15), both associated with enhanced tumor growth in the Brandes study, 2 were not significantly associated with breast cancer. No indication of effect modification by menopausal status was apparent for regular use of antihistamines (data not shown).…”

Section: Resultsmentioning

confidence: 91%

“…1 The other study found that mice injected with melanoma or fibrosarcoma cells experienced accelerated tumor growth with the administration of human equivalent doses of the antihistamines loratidine and astemizole (for melanoma and fibrosarcoma), and hydroxyzine (for melanoma). 2 Animal data are suggestive of the effect that these medications might have on humans. As a result, following the publication of these results, epidemiologic studies have used human populations to explore the hypothesis that there may be a relationship between cancer risk and the use of antidepressants, and, to a lesser degree, antihistamines.…”

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confidence: 99%

Antihistamine use and breast cancer risk

Nadalin

Cotterchio

Kreiger

2003

Intl Journal of Cancer

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Antihistamines are structurally similar to DPPE, a tamoxifen derivative known to promote tumor growth, and to antidepressants. Animal experiments have linked certain antihistamines and antidepressants with enhanced tumor growth in mice. The few epidemiologic studies examining antihistamine use have not indicated an increased risk. In light of suggestive animal data, structural similarities between antihistamines and DPPE, the widespread use of antihistamines, and the lack of epidemiologic investigation into their use and breast cancer risk, it is important to examine this issue. Antihistamines are available as both prescription and nonprescription medications, and are commonly used for the treatment of allergic symptoms (e.g., for relief from hayfever), for cold symptoms or for insomnia. Both antihistamines and tricyclic antidepressants are structurally similar to DPPE [N,N-diethyl-2-(4-(phenylmethyl)phenoxy) ethanamine HC1], a tamoxifen derivative known to promote tumor growth by binding to intracellular histamine receptors. This structural similarity to DPPE led to 2 widely cited rodent studies led by Brandes, 1,2 which suggested that both antihistamines and antidepressants promote accelerated tumor growth. 1,2 . One study found that inoculated fibrosarcomas and melanomas, and carcinogen (DMBA) induced mammary tumors were promoted by the administration of the antidepressants fluoxetine and amitriptyline. 1 The other study found that mice injected with melanoma or fibrosarcoma cells experienced accelerated tumor growth with the administration of human equivalent doses of the antihistamines loratidine and astemizole (for melanoma and fibrosarcoma), and hydroxyzine (for melanoma). 2 Animal data are suggestive of the effect that these medications might have on humans. As a result, following the publication of these results, epidemiologic studies have used human populations to explore the hypothesis that there may be a relationship between cancer risk and the use of antidepressants, and, to a lesser degree, antihistamines. Although not consistent, these studies have shown that the use of some antidepressants may be associated with an increased risk for a number of cancers, including breast. 3,4 Conversely, antihistamine use has not been associated with an increased cancer risk for breast, colon or all cancers, cancer recurrence (of melanoma, breast, or colon cancers) or for second primary cancers. 5-7 These reassuring results regarding antihistamines are not definitive, however, as the number of studies examining this relationship is small; one was limited to an examination of prescription antihistamine use, and another considered only cancer recurrence and second primary cancers. 6,7 To our knowledge, there are no other epidemiologic studies examining the relationship between nonprescription antihistamine use and the risk of cancer.Given the high incidence of breast cancer, widespread use of antihistamines, lack of epidemiologic investigation into the association, suggestive animal data and its structural similari...

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Enhanced Cancer Growth in Mice Administered Daily Human-Equivalent Doses of Some H1-Antihistamines: Predictive In Vitro Correlates

Abstract: These in vitro tests may prove valuable to screen potential tumor growth promoters.

Cited by 45 publications

References 0 publications

Nonhormonal drugs and cancer.

Nonhormonal drugs and cancer.

Translationally controlled tumor protein is a target of tumor reversion

Antihistamine use and breast cancer risk

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