Major Research Findings

Etoposide is an anti-cancer drug that has been shown to have serious adverse effects on male reproductive function. 4 found that etoposide administration increased malondialdehyde (MDA), decreased superoxide dismutase (SOD), collapsed Sertoli cell vimentin filaments and caused ultrastructural degenerative changes in both Sertoli cells and ESs in rat testes. However, omega-3 polyunsaturated fatty acids (ω-3 PUFAs) and selenium (Se), both known as anti-inflammatory, anti-apoptotic and anti-oxidant agents, were shown to have ameliorative effects on these changes, with selenium showing more potent effects than omega-3.

In contrast, 3 found that loss of function of the tumor suppressor gene p53 resulted in increased DNA damage induced by etoposide, a DNA topoisomerase II (Top2) poison. This study showed that cells lacking a fully functional p53 exhibited resistance to etoposide in cell growth assays, but were hypersensitive in clonogenic survival assays. This complex role of p53 led researchers to identify ATR as a gene whose reduced expression resulted in enhanced synthetic lethality upon etoposide treatment of p53 defective cells. Furthermore, decreased expression of ATR was shown to sensitize p53-defective cells to etoposide in all assays and generated elevated levels of Top2cc in both p53 proficient and deficient cells.

Etoposide was also shown to induce contrasting immunogenic effects in acute myeloid leukemia (AML) cells. 9 found that etoposide, unlike daunorubicin, does not induce immunogenic cell death (ICD) in AML cells. Immunogenic cell death is a process that involves the activation of immune cells by dying cancer cells, resulting in an anti-tumor immune response. This finding suggests that etoposide may have different immunological effects than other anti-cancer drugs.

In another study, 10 investigated the effects of three common genotoxic agents, etoposide, bleomycin, and ethyl methanesulfonate (EMS), on cultured CHO cells. While all three agents caused DNA strand breaks detected by the comet assay, only bleomycin-induced oxidative DNA nucleobase lesions could be detected by GC-MS/MS. This demonstrated that, while GC-MS/MS has limitations in detecting genotoxic effects, it can be used for selected chemical genotoxins that contribute to oxidizing processes. The comet assay, used in combination with GC-MS/MS, is a more useful approach to screen a wide range of chemical genotoxins and monitor other DNA-damaging factors.

7 investigated the combination treatment of CI-994, an HDAC1 inhibitor, with etoposide in atypical teratoid/rhabdoid tumor (AT/RT) cells and found that the combination treatment potentiated anti-cancer effects through a Topoisomerase II-dependent mechanism. AT/RT is a malignant tumor that commonly occurs in children and currently has no curative chemotherapy regimen. This research suggests that the combination therapy of CI-994 and etoposide could be a novel treatment strategy for AT/RT.

1 investigated the effects of bleomycin, etoposide, and cisplatin (BEP) chemotherapy on rat testes and found that BEP treatment significantly increased sperm DNA fragmentation, sperm morphological abnormalities, decreased serum testosterone levels, sperm count, and caused testicular atrophy. However, the study also found that glutathione administration could alleviate these adverse effects, suggesting that exogenous glutathione may prevent the deterioration of male reproductive functions by mitigating the detrimental effects of BEP treatment.

5 showed that gamma-tocotrienol synergistically promotes the anti-proliferative and pro-apoptotic effects of etoposide on breast cancer cell lines. Gamma-tocotrienol, an isomer of vitamin E, is known to have antioxidant properties. This study found that gamma-tocotrienol, by enhancing the effects of etoposide, can suppress the growth of breast cancer cells and induce apoptosis.

6 investigated the synergistic anti-cancer effects of the combination of silibinin and etoposide against human breast carcinoma MCF-7 and MDA-MB-231 cell lines. Silibinin, a flavonoid extracted from milk thistle, is known to have antioxidant and anti-cancer properties. This study found that silibinin, by enhancing the effects of etoposide, can suppress the growth of breast cancer cells and induce apoptosis.

11 reported successful treatment of mogamulizumab-resistant mycosis fungoides with the combination therapy of mogamulizumab plus etoposide. Mogamulizumab is a monoclonal antibody that targets CCR4+ lymphoma cells and is used to treat advanced cutaneous T-cell lymphoma (CTCL). This study found that the combination therapy with etoposide enhances the anti-tumor effect of mogamulizumab in mogamulizumab-resistant mycosis fungoides patients.

2 investigated the effects of etoposide combined with cisplatin on prognosis of patients with castration-resistant prostate cancer (CRPC) who failed castration treatment. The study found that the combination therapy improved the overall survival of the patients. However, this study was small and further large-scale studies are needed to confirm this finding.

8 investigated the mechanism underlying etoposide resistance in neuroblastoma and found that etoposide upregulated growth hormone receptor (GHR) expression levels in etoposide-resistant neuroblastoma cells. GHR is a receptor involved in growth hormone signaling. This study showed that GHR knockdown enhanced the inhibitory effects of etoposide on cell viability, sensitized cells to etoposide, and enhanced the inhibitory effect of etoposide on cell migration. This suggests that GHR is a key factor in etoposide resistance.

Benefits and Risks

Benefit Summary

Etoposide is an effective anti-cancer drug used to treat many types of cancer. It is known to be effective in treating small cell lung cancer, ovarian cancer, leukemia, and neuroblastoma, among others. Etoposide can also be used in combination with other anti-cancer drugs to enhance its efficacy.

Risk Summary

Etoposide is known to have significant side effects. The main side effects include myelosuppression, gastrointestinal disorders, liver dysfunction, and allergic reactions. Additionally, etoposide can have adverse effects on the fetus, so it should not be used during pregnancy.

Comparison Across Studies

Commonalities in Studies

All these studies investigated the effects of etoposide, and they commonly showed that etoposide is highly effective against cancer cells but also has strong side effects. Furthermore, several substances have been identified that could enhance the effects of etoposide or reduce its side effects.

Differences in Studies

These studies used different cancer types, different treatments, and different evaluation methods. Therefore, it is difficult to directly compare the results. Additionally, some studies are small, making it difficult to generalize their results. Furthermore, some studies involved animals rather than humans, making it difficult to guarantee their effects on humans.

Consistency and Contradictions in Results

While the results of these studies suggest that etoposide is an effective anti-cancer drug, they also indicate that it has strong side effects. Several substances have been identified that could enhance the effects of etoposide or reduce its side effects, but their efficacy is not conclusive. Additionally, there are inconsistencies in the research findings, so further research is needed to assess the efficacy and safety of etoposide.

Considerations for Application in Daily Life

Etoposide is a strong anti-cancer drug with significant side effects. It is crucial to use it properly under the guidance of a doctor. During etoposide treatment, regular blood tests are necessary to monitor for side effects. Additionally, etoposide can have adverse effects on the fetus, so it should not be used by pregnant women. Furthermore, etoposide can interact with other medications, so it is important to consult with a doctor if you are taking other medications.

Limitations of Current Research

All these studies were small-scale trials, making it difficult to generalize their results. Additionally, some studies involved animals rather than humans, making it difficult to guarantee their effects on humans. Furthermore, differences in research methods and evaluation methods make it difficult to directly compare the results.

Future Research Directions

To assess the efficacy and safety of etoposide, more large-scale studies are needed. Additionally, new treatment methods need to be developed to mitigate the side effects of etoposide. Furthermore, it is important to investigate how etoposide affects different cancer types.

Conclusion

Etoposide is an effective anti-cancer drug used to treat many types of cancer. However, it also has significant side effects. Further research is needed to evaluate the efficacy and safety of etoposide. If you are considering using etoposide, it is important to consult with your doctor and understand the risks and benefits involved.