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Encapsulation of Cancer Therapeutic Agent Dacarbazine Using Nanostructured Lipid Carrier
Published on: April 26, 2016
Dacarbazine induces genotoxic and cytotoxic germ cell damage with concomitant decrease in testosterone and increase
S Ganesh Kumar1, K Narayana, K L Bairy
1Department of Physiology and Anatomy, Melaka Manipal Medical College, International Centre for Health Sciences, Madhav Nagar, Manipal 576104, India.
Abstract:
Treatment of cancers with cytotoxic agents such as alkylating drugs often, but not always results in transient to permanent testicular dysfunction. The present study was planned to investigate the effects of dacarbazine [5-(3,3-dimethyltriazeno) imidazole-4-carboxamide] on testicular function in mice. Swiss albino mice (9-12 weeks old) were treated with 0, 5, 25, 50, or 100mg/kg body weight/day dacarbazine (i.p.) for 5 days at intervals of 24h between treatments. Mice were sacrificed on days 7, 14, 21, 28, 35, 49, and 70 after the last treatment (6 mice/dose/sample time), and the epididymal sperm count, sperm motility, sperm morphology, testicular histopathology (qualitative histopathology, seminiferous tubular diameter and epithelial height), and intra-testicular levels of testosterone and lactate dehydrogenase were assessed. Dacarbazine decreased the body weight only on day 28 at 25mg/kg dose-level, but increased the paired testes weights at 50mg/kg on day 7, at 25-100mg/kg on day 14, and at 25 and 50mg/kg on day 21 (P<0.05-0.01; one-way ANOVA and Bonferroni's post hoc test). The sperm count was decreased on all sampling days except at 5 and 25mg/kg dose-levels on day 70, but with severe oligospermia on days 28 and 35 (P<0.05-0.001). The sperm motility was decreased at 100mg/kg on days 14 and 21, at 5, 25, and 100mg/kg on day 28, and at all dose-levels on day 35 (P<0.05-0.001). Dacarbazine induced both head and tail abnormalities and some sperms with cytoplasmic droplets, but significant increase was seen in all dose groups on days 14 and 21, and at 100mg/kg dose-level on day 35. Drug-induced epithelial sloughing was seen on days 14-35 and other histopathological changes observed were vacuoles and abnormal cells. The STD was increased at 25-100mg/kg on day 7, at all dose-levels on day 14, at 50-100mg/kg on days 21 and 28, but without any effects on days 35-70 (P<0.05-0.001), and the tubular lumen was found dilated. The SE was increased on days 7, 21 and 28 at 100mg/kg and on day 14 at 50-100mg/kg. Dacarbazine reduced the intra-testicular testosterone level at 100mg/kg on day 7, at 5, 50 and 100mg/kg on day 14, at all dose-levels on days 21, 28, and 35, and at 50mg/kg on day 49 (P<0.05-0.001). The intra-testicular lactate dehydrogenase concentration increased at all dose-levels up to day 35, but without any effect on days 49 and 70 (P<0.05-0.001). There was no particular dose-response of dacarbazine on any parameters tested. The sperm count (except on day 7-positive correlation; Pearson product moment correlation) or sperm motility did not have any relation but increase in abnormal sperms showed negative correlation with decrease in testosterone level on days 7, 21 and 28. Decrease in sperm count was in negative correlation on days 14 and 35, and increase in abnormal sperms showed positive correlation on day 35 with increase in LDH level. Finally, the decrease in sperm motility had no correlation with increase in abnormal sperm shapes. We conclude that dacarbazine is genotoxic and cytotoxic to the mouse testis in a transient fashion, and these effects are exerted along with decrease in testosterone and increase in lactate dehydrogenase levels in the testis.
Insights
Dacarbazine, a cancer treatment drug, causes temporary testicular damage in mice, affecting sperm count, motility, and morphology. These effects are linked to reduced testosterone and increased lactate dehydrogenase levels.
Area of Science:
- Toxicology
- Reproductive Biology
- Cancer Therapeutics
Background:
- Cytotoxic chemotherapy agents, including alkylating drugs, can induce transient or permanent testicular dysfunction.
- Understanding the specific impact of agents like dacarbazine on male reproductive health is crucial for patient counseling and fertility preservation strategies.
Purpose of the Study:
- To investigate the effects of dacarbazine on various parameters of testicular function in a mouse model.
- To assess the dose-dependent and time-course effects of dacarbazine on sperm parameters, testicular histology, and key biochemical markers.
Main Methods:
- Swiss albino mice were administered varying doses of dacarbazine (0-100 mg/kg) intraperitoneally for five consecutive days.
- Following treatment, mice were euthanized at multiple time points (7-70 days) to evaluate epididymal sperm count, motility, morphology, testicular histopathology, and intra-testicular testosterone and lactate dehydrogenase (LDH) levels.
Main Results:
- Dacarbazine treatment led to significant reductions in sperm count and motility, and increased sperm abnormalities.
- Histopathological examination revealed drug-induced damage, including epithelial sloughing and vacuoles, alongside increased seminiferous tubular diameter and epithelial height.
- A notable decrease in intra-testicular testosterone levels and an increase in LDH concentration were observed, particularly at higher doses and earlier time points.
Conclusions:
- Dacarbazine exhibits transient genotoxic and cytotoxic effects on mouse testes.
- These testicular dysfunctions are associated with altered testosterone synthesis and elevated LDH levels within the testis.
- The findings highlight the potential for dacarbazine to impair male reproductive function, emphasizing the need for further research into protective strategies.
