Ototoxicity among cisplatin, carboplatin, and oxaliplatin in zebrafish model.

Platinum-based antineoplastic drugs, including cisplatin, carboplatin, and oxaliplatin, are widely used in the treatment of various cancers. Ototoxicity is a common adverse effect of platinum-based drugs. Ototoxicity leads to irreversible hearing impairment. We hypothesize that different platinum-based drugs exhibit varying ototoxic concentrations, time effects, and ototoxic mechanisms. We tested this hypothesis by using a zebrafish model (pvalb3b: TagGFP) to assess the viability of hair cells collected from zebrafish larvae. Cisplatin, carboplatin, and oxaliplatin were administered at dosages of 100, 200, or 400 µM, and the ototoxic effects of these drugs were assessed 1, 2, or 3 h after administration. Fm4-64 and a TUNEL assay were used to label the membranes of living hair cells and to detect cell apoptosis, respectively. We observed that >50% of hair cells were damaged at 1 h after cisplatin (100 µM) exposure, and this ototoxic effect increased at higher dosages and over time. Owing to the smaller ototoxic effects of carboplatin and oxaliplatin, we conducted higher-strength and longer-duration experiments with these drugs. Neither carboplatin nor oxaliplatin was obviously ototoxic, even at 1600 µM and after 6 h. Moreover, only cisplatin damaged the membranes of the hair cells. Cell apoptosis and significantly increased antioxidant gene expression were observed in only the cisplatin group. In conclusion, cisplatin significantly damages sensory hair cells and has notable dosage and time effects. Carboplatin and oxaliplatin are less ototoxic than cisplatin, likely due to having different ototoxic mechanisms than cisplatin.

Exposure to select PFAS and PFAS mixtures alters response to platinum-based chemotherapy in endometrial cancer cell lines.

BACKGROUND: Exposure to per- and poly-fluoroalkyl substances (PFAS) has been associated with significant alterations in female reproductive health. These include changes in menstrual cyclicity, timing of menarche and menopause, and fertility outcomes, as well as increased risk of endometriosis, all of which may contribute to an increased risk of endometrial cancer. The effect of PFAS on endometrial cancer cells, specifically altered treatment response and biology, however, remains poorly studied. Like other gynecologic malignancies, a key contributor to lethality in endometrial cancer is resistance to chemotherapeutics, specifically to platinum-based agents that are used as the standard of care for patients with advanced-stage and/or recurrent disease. OBJECTIVES: To explore the effect of environmental exposures, specifically PFAS, on platinum-based chemotherapy response and mitochondrial function in endometrial cancer. METHODS: HEC-1 and Ishikawa endometrial cancer cells were exposed to sub-cytotoxic nanomolar and micromolar concentrations of PFAS/PFAS mixtures and were treated with platinum-based chemotherapy. Survival fraction was measured 48-h post-chemotherapy treatment. Mitochondrial membrane potential was evaluated in both cell lines following exposure to PFAS ± chemotherapy treatment. RESULTS: HEC-1 and Ishikawa cells displayed differing outcomes after PFAS exposure and chemotherapy treatment. Cells exposed to PFAS appeared to be less sensitive to carboplatin, with instances of increased survival fraction, indicative of platinum resistance, observed in HEC-1 cells. In Ishikawa cells treated with cisplatin, PFAS mixture exposure significantly decreased survival fraction. In both cell lines, increases in mitochondrial membrane potential were observed post-PFAS exposure ± chemotherapy treatment. DISCUSSION: Exposure of endometrial cancer cell lines to PFAS/PFAS mixtures had varying effects on response to platinum-based chemotherapies. Increased survival fraction post-PFAS + carboplatin treatment suggests platinum resistance, while decreased survival fraction post-PFAS mixture + cisplatin exposure suggests enhanced therapeutic efficacy. Regardless of chemotherapy sensitivity status, mitochondrial membrane potential findings suggest that PFAS exposure may affect endometrial cancer cell mitochondrial functioning and should be explored further.

Platinum-based chemotherapy induces demyelination of Schwann cells in oral squamous cell carcinoma treatment.

BACKGROUND: Cisplatin, carboplatin, and oxaliplatin are the only three platinum-based antineoplastic drugs that have been accepted worldwide for treating various cancers. Up to 83.6% of patients treated with platinum-based antineoplastic drugs will develop chemotherapy-induced peripheral neuropathy (CIPN), manifesting as sensory paresthesias, dysesthesias, and hypoesthesias that can cause significant adverse impact to daily activities. AIM: To investigate how these three platinum-based drugs affect mitochondrial function and myelination state of Schwann cells and the signalling pathway involved. METHOD: 2 µM Cisplatin, 20 µM carboplatin, and 1 µM oxaliplatin were used to inhibit the growth of CAL-27 by 20% respectively. These drugs were then used to induce chemotherapy-induced peripheral neuropathy in Rat Schwann Cells (RSC96). The changes in cell metabolism and myelin formation in RSC96 were investigated. RESULT: Cisplatin and carboplatin, but not oxaliplatin increased intracellular and mitochondrial reactive oxygen species in RSC96. Only Cisplatin and carboplatin decreased mitochondrial membrane potential (ΔΨm) and ATP production in RSC96. Both Cisplatin and carboplatin led to demyelination of RSC96, characterized by increased expression of p75NTR and decreased expression of myelin protein zero (MPZ). CONCLUSION: Cisplatin and carboplatin, but not oxaliplatin, caused mitochondrial dysfunction and induced demyelination in RSC96 while showing similar toxicity to head and neck cancer cells. Oxaliplatin may be a potential chemotherapy drug to prevent CIPN in patients with head and neck cancer.

Ameliorative Effects of Alpha-tocopherol in Carboplatin Induced Toxicity on Histomorphology of Renal Cortex in Rats.

OBJECTIVE: To evaluate the histomorphological response of alpha-tocopherol co-administration with carboplatin chemotherapy. STUDY DESIGN: A laboratory-based experimental study. Place and Duration of the Study: Anatomy Department, Army Medical College / National University of Medical Sciences (NUMS), Rawalpindi, Pakistan, from January to December 2021. METHODOLOGY: Thirty adult Sprague-Dawley rats were divided into three groups of ten rats each. Control group A received normal diet and water, experimental group B was administered single injection of carboplatin 2.5 mg/Kg intraperitoneally; and experimental group C along with carboplatin injection also received alpha-tocopherol 62.7 mg/Kg daily. At the end of 12 weeks, the euthanasia of animals was done and kidneys were dissected out. Right-sided kidneys were stained with Haematoxylin and Eosin. Micrometry was done to measure the diameters of renal cortical tubules and renal corpuscles. RESULTS: The proximal and distal tubular and luminal diameter and transvertical diameter of renal corpuscle were increased in group B as compared to control group A. In group C, the proximal and distal tubular diameters were 5.175 ± 0.39 µm and 3.88 ± 0.364 µm, respectively; proximal and distal luminal diameters were 2.67 ± 0.35 µm and 1.64 ± 0.24 µm, respectively and transvertical diameter of renal corpuscle was 12.16 ± 0.870 µm. These values were less than experimental group B and closer to that of control group A. CONCLUSION: Renal microscopic parameters showed improvement in the group administered with alpha-tocopherol. Therefore, alpha-tocopherol has ameliorative effects on carboplatin-induced renal damage. KEY WORDS: Alpha-tocopherol, Carboplatin, Renal corpuscle, Tubules.

Estrone-Conjugated PEGylated Liposome Co-Loaded Paclitaxel and Carboplatin Improve Anti-Tumor Efficacy in Ovarian Cancer and Reduce Acute Toxicity of Chemo-Drugs.

Purpose: Ovarian cancer is the most lethal gynecologic malignancy. The combination of paclitaxel (PTX) and carboplatin (CBP) is the first-line remedy for clinical ovarian cancer. However, due to the limitations of adverse reaction and lacking of targeting ability, the chemotherapy of ovarian cancer is still poorly effective. Here, a novel estrone (ES)-conjugated PEGylated liposome co-loaded PTX and CBP (ES-PEG-Lip-PTX/CBP) was designed for overcoming the above disadvantages. Methods: ES-PEG-Lip-PTX/CBP was prepared by film hydration method and could recognize estrogen receptor (ER) over-expressing on the surface of SKOV-3 cells. The characterizations, stability and in vitro release of ES-PEG-Lip-PTX/CBP were studied. In vitro cellular uptake and its mechanism were observed by fluorescence microscope. In vivo targeting effect in tumor-bearing mice was determined. Pharmacokinetics and biodistribution were studied in ICR mice. In vitro cytotoxicity and in vivo anti-tumor efficacy were evaluated on SKOV-3 cells and tumor-bearing mice, respectively. Finally, the acute toxicity in ICR mice was explored for assessing the preliminary safety of ES-PEG-Lip-PTX/CBP. Results: Our results showed that ES-PEG-Lip-PTX/CBP was spherical shape without aggregation. ES-PEG-Lip-PTX/CBP exhibited the optimum targeting effect on uptake in vitro and in vivo. The pharmacokinetics demonstrated ES-PEG-Lip-PTX/CBP had improved the pharmacokinetic behavior. In vitro cytotoxicity showed that ES-PEG-Lip-PTX/CBP maximally inhibited SKOV-3 cell proliferation and its IC50 values was 1.6 times lower than that of non-ES conjugated liposomes at 72 h. The in vivo anti-tumor efficacy study demonstrated that ES-PEG-Lip-PTX/CBP could lead strong SKOV-3 tumor growth suppression with a tumor volume inhibitory rate of 81.8%. Meanwhile, acute toxicity studies confirmed that ES-PEG-Lip-PTX/CBP significantly reduced the toxicity of the chemo drugs. Conclusion: ES-PEG-Lip-PTX/CBP was successfully prepared with an optimal physicochemical and ER targeting property. The data of pharmacokinetics, anti-tumor efficacy and safety study indicated that ES-PEG-Lip-PTX/CBP could become a promising therapeutic formulation for human ovarian cancer in the future clinic.

Effect of Selective Carboplatin-Induced Inner Hair Cell Loss on Temporal Integration in Chinchillas.

Integration of acoustic information over time is essential for processing complex stimuli, such as speech, due to its continuous variability along the time domain. In both humans and animals, perception of acoustic stimuli is a function of both stimulus intensity and duration. For brief acoustic stimuli, as duration increases, thresholds decrease by approximately 3 dB for every doubling in duration until stimulus duration reaches 500 ms, a phenomenon known as temporal integration. Although hearing loss and damage to outer hair cells (OHC) have been shown to alter temporal integration in some studies, the role of cochlear inner hair cells (IHC) on temporal integration is unknown. Because IHC transmit nearly all acoustic information to the central auditory system and are believed to code both intensity and timing information, these sensory cells likely play a critical role in temporal integration. To test the hypothesis that selective IHC loss degrades the temporal integration function, behaviorally trained chinchillas were treated with carboplatin, a drug known to selectively destroy IHC with little to no effect on OHC in this species. Pure-tone thresholds were assessed across frequencies (1, 2, 4, 8, 12 kHz) as a function of signal duration (500, 100, 50, 10, and 5 ms). Baseline testing showed a significant effect of duration on thresholds. Threshold decreased as a function of increasing duration, as expected. Carboplatin treatment (75 mg/kg) produced a moderate to severe loss of IHC (45-85%) with little-to-no loss of OHC. Contrary to our hypothesis, post-carboplatin temporal integration thresholds showed no significant differences from baseline regardless of stimulus duration or frequency. These data suggest that few IHC are necessary for temporal integration of simple stimuli. Temporal integration may be sensitive to loss of OHC and loss of cochlear non-linearities but does not appear to be sensitive to selective IHC loss.

Protective effect of chrysin, a flavonoid, on the genotoxic activity of carboplatin in mice.

Carboplatin is amongst the most commonly used anticancer drugs for the management of several human malignancies. However, it has displayed genotoxic properties against normal cells. Evaluation of natural products for their protective effects against chemotherapeutic drug induced toxicity has been growing in recent years. A naturally occurring flavonoid, chrysin, has strong antioxidant abilities and protects against DNA impairment. This study used multiple assays to evaluate the levels of damage to DNA in normal cells and to examine any possible protective role of chrysin against such damage. Male BALB/c mice were administered chrysin orally in two doses of 20 and 40 mg/kg for 10 consecutive days and then a single injection of carboplatin [90 mg/kg body weight (b.w.)] was administered intraperitoneally to induce carboplatin toxicity. 24 h after the carboplatin injection, mice were sacrificed. DNA damage was evaluated using several genotoxicity tests (8-Hydroxydeoxy-guanosine marker, comet assay, micronucleus test, and chromosomal aberration assay) to identify diverse types of damage to the DNA. The results suggest that pretreatment with chrysin significantly decreased the level of DNA damage caused by carboplatin probably due to its potent antioxidant traits. Therefore, chrysin can be considered to be developed as a chemoprotective agent against chemotherapy associated side-effects.

Pharmacokinetic and safety assessment of carboplatin-impregnated calcium sulfate hemihydrate beads in eight rats.

OBJECTIVE: Evaluate local tissue toxicity and plasma platinum (Pt) in vivo after subcutaneous implantation of carboplatin-impregnated calcium sulfate hemihydrate (CI-CSH) beads. STUDY DESIGN: In vivo experimental study. ANIMALS: Eight male Sprague-Dawley rats. METHODS: CI-CSH beads were implanted subcutaneously (5 mg carboplatin/rat; 13.5 mg/kg carboplatin; 7.08 mg/kg Pt; 1.18 mg/m2 Pt) in eight rats (d0). Wound healing (daily), radiographic bead dissolution (weekly), systemic Pt uptake (plasma-Pt), local tissue Pt (d28), and histologic changes compared to nonincised and incised catheterization sites (d28) were assessed. Blood and tissue samples were analyzed by inductively coupled plasma mass spectrometry for Pt, and pharmacokinetic analysis was performed using noncompartmental methods. RESULTS: One rat died at d10, the remainder survived until d28. No wound complications were seen. The CI-CSH implantation site had higher histopathology scores than the other sites for necrosis (p = .013) and fibrosis (p = .013). Beads decreased in density radiographically (d0 to d28) (p = .062). Peak plasma-Pt concentration was 225.78 ng/ml at 12 h, and decreased over time, but Pt was still detectable on d28. The elimination half-life was 5.03 ± 1.13 days. Only 1.69% of implanted Pt remained in the beads at d28. CONCLUSIONS: CI-CSH beads incited microscopic mild inflammation but wound healing was not impaired. Pt was absorbed systemically and the release from the beads was near complete at d28. CLINICAL SIGNIFICANCE: Piled CI-CSH bead implantation is well tolerated in rats with similar elution profile as previously described. Beads were radiographically visible at d28. Minimal Pt was detected systemically suggesting Pt release does not match bead dissolution.

Comparisons of segment-specific toxicity of platinum-based agents and cadmium using S1, S2, and S3 cells derived from mouse kidney proximal tubules.

Renal toxicants such as cisplatin and cadmium cause segment-specific damages in kidney proximal tubules. Recently, we established an in vitro experimental system for evaluating segment-specific toxicity and transport of chemicals using immortalized S1, S2, and S3 cells derived from the S1, S2, and S3 regions of mouse kidney proximal tubules. In the present study, we examined the toxicity and accumulation of cisplatin, carboplatin, oxaliplatin, and cadmium in S1, S2, and S3 cells. We found that not only cisplatin but also carboplatin and oxaliplatin exhibited higher lethal toxicity in S3 cells than in S1 and S2 cells. At sublethal doses, cisplatin showed delayed induction of Kim-1 and clusterin on days 3 and 6, which may reflect the latent renal toxicity of cisplatin in vivo. The high sensitivities of S3 cells to the platinum-based agents were not due to the high accumulation of Pt in S3 cells. Exposure to cadmium resulted in similar toxicity among these cells, suggesting that S3 cells were not sensitive to any renal toxicants. Thus, the utilization of S1, S2, and S3 cells may provide a useful tool for the in vitro evaluation of the proximal tubule segment-specific toxicity of chemicals.

Berberine inhibits chemotherapy-exacerbated ovarian cancer stem cell-like characteristics and metastasis through GLI1.

Despite the remarkable clinical response in ovarian cancer therapy, the distinctively high metastasis rate is still a barrier to achieve satisfying prognosis. Our study aimed to decipher the role of berberine in inhibiting chemotherapy-exacerbated ovarian cancer metastasis. We found that chemotherapy exacerbated the migration and cancer stem cell (CSC)-like characteristics through transcriptional factor GLI1, which regulated the pluripotency-associated gene BMI1 and the epithelial-mesenchymal transition (EMT) markers Vimentin and Snail. Berberine could not only down-regulate CSC-like characteristics but also reverse EMT and migration through inhibiting chemotherapy-activated GLI1/BMI1 signaling pathway. Together, our study revealed the pivotal role of berberine in overcoming chemotherapy-exacerbated ovarian cancer metastasis, thereby provided a potential adjuvant therapeutic agent in combination with chemotherapeutics to prevent metastasis during ovarian cancer chemotherapy.

Chemopreventive effect of α-hederin/carboplatin combination against experimental colon hyperplasia and impact on JNK signaling.

Colon cancer is the commonest cancer worldwide. α-Hederin is a monodesmosidic triterpenoid saponin possessing diverse pharmacological activities. The running experiment was designed to test the chemopreventive activity of α-hederin when used as an adjuvant to carboplatin in an experimental model of mouse colon hyperplasia induced by 1,2-dimethylhydrazine (DMH). Fifty male Swiss albino mice were classified into five groups: group (I): saline group, group (II): DMH-induced colon hyperplasia control group, group (III): DMH + carboplatin (5 mg/kg) group, group (IV): DMH + α-hederin (80 mg/kg) group, and group (V): DMH + carboplatin (5 mg/kg)+α-hederin (80 mg/kg) group. Analyzing of colonic tissue indicated that the disease control group showed higher colon levels of phospho-PI3K to total-PI3K, phospho-AKT to total-AKT and cyclin D1 concurrent with lower phospho-JNK/total JNK ratio and caspase 3. However, treatment with α-hederin, in combination with carboplatin, favorably ameliorated phosphorylation of PI3K/AKT/JNK proteins, increased colon caspase 3 and downregulated cyclin D1. Microscopically, α-hederin, in combination with carboplatin, produced the most reduction in the histologic hyperplasia score, enhanced the goblet cell survival in periodic acid Schiff staining and reduced proliferation (Ki-67 immunostaining) in the current colon hyperplasia model. Collectively, the current study highlighted for the first time that using α-hederin as an adjuvant to carboplatin enhanced its chemopreventive activity, improved JNK signaling and increased apoptosis. Hence, further studies are warranted to test α-hederin as a promising candidate with chemotherapeutic agents in treating colon cancer.

Evaluation of toxic effects of platinum-based antineoplastic drugs (cisplatin, carboplatin and oxaliplatin) on green alga Chlorella vulgaris.

Platinum-based antineoplastic drugs (PBADs) enter the environment via hospital and municipal wastes as reactive and highly toxic molecules. Chlorella vulgaris is a freshwater microalgae and is used as an excellent aquatic model for toxicity assessment. In the present study, the toxicity of PBADs to C. vulgaris was investigated for better understanding of PBADs environmental toxicity. The algae were cultured in Bold´s Basal Medium (BBM) and exposed to different concentrations of PBADs for 48, 72 and 96 h. Then, cell proliferation, the synthesis of photosynthetic pigments, protein content, malondialdehyde (MDA) release and antioxidant potential were determined. IC50 s of cisplatin, carboplatin and oxaliplatin for 96 h of exposure were 106.2, 124.3 and 153.9 mg/L respectively. Cell proliferation, synthesis of chlorophyll a, chlorophyll b and algal protein content significantly decreased in a time and dose-dependent manner. The release of MDA to culture media significantly increased and antioxidant potential decreased. Cisplatin showed more toxic effects on C. vulgaris compared to carboplatin and oxaliplatin indicating its severe toxicity for marine organisms. PBADs induce their toxic effects in algal cells via the interaction with DNA, production of free radicals (such as reactive oxygen species), lipid peroxidation and cell wall damages. Due to these toxic effects of PBADs for various environmental organisms, there must be severe restriction on their release into the environment.

Optimization of cell viability assays to improve replicability and reproducibility of cancer drug sensitivity screens.

Cancer drug development has been riddled with high attrition rates, in part, due to poor reproducibility of preclinical models for drug discovery. Poor experimental design and lack of scientific transparency may cause experimental biases that in turn affect data quality, robustness and reproducibility. Here, we pinpoint sources of experimental variability in conventional 2D cell-based cancer drug screens to determine the effect of confounders on cell viability for MCF7 and HCC38 breast cancer cell lines treated with platinum agents (cisplatin and carboplatin) and a proteasome inhibitor (bortezomib). Variance component analysis demonstrated that variations in cell viability were primarily associated with the choice of pharmaceutical drug and cell line, and less likely to be due to the type of growth medium or assay incubation time. Furthermore, careful consideration should be given to different methods of storing diluted pharmaceutical drugs and use of DMSO controls due to the potential risk of evaporation and the subsequent effect on dose-response curves. Optimization of experimental parameters not only improved data quality substantially but also resulted in reproducible results for bortezomib- and cisplatin-treated HCC38, MCF7, MCF-10A, and MDA-MB-436 cells. Taken together, these findings indicate that replicability (the same analyst re-performs the same experiment multiple times) and reproducibility (different analysts perform the same experiment using different experimental conditions) for cell-based drug screens can be improved by identifying potential confounders and subsequent optimization of experimental parameters for each cell line.

The expression of copper transporters associated with the ototoxicity induced by platinum-based chemotherapeutic agents.

BACKGROUND: Antitumor agents based on platinum have gained a well-established place in the treatment of several forms of cancer. Their efficiency is hampered by serious toxic effects against healthy tissues as well. Ototoxicity is a serious side effect leading to hearing impairment and represents an important issue affecting the patients' quality of life. The currently used platinum chemotherapeutics exert different toxicity towards cochlear cells. The aim of our study was to answer some questions regarding the differential uptake and cellular pharmacodynamics of Cisplatin (CDDP), Carboplatin (CBDCA) and Oxaliplatin (L-OHP) in the HEI-OC1 cochlear cell line. METHODS: We studied the expression of copper transporters CTR1, ATP7A and ATP7B which are presumably involved in the uptake, cellular transport and efflux of platinum compounds by immunofluorescence microscopy and flow-cytometry. The cellular uptake of the compounds was evaluated through the determination of intracellular platinum concentration by atomic absorption spectroscopy. The effects of the treatment of HEI-OC1 cells with platinum compounds were also evaluated: cytotoxicity with the Cell Titer Blue viability test, formation of reactive oxygen species with 2',7' -dichlorofluorescein diacetate, genotoxicity with the comet assay and apoptosis with the cleaved PARP ELISA test. RESULTS: CTR1, ATP7A and ATP7B were all expressed by HEI-OC1 cells. The treatment with the platinum compounds led to a modulation of their expression, manifested in a differential platinum uptake. Treatment with Cisplatin led to the highest intracellular concentration of platinum compared to Oxaliplatin and Carboplatin at the same dose. Treatment with CuSO4 reduced platinum uptake of all the compounds, significantly in the case of Cisplatin and Carboplatin. CDDP was the most cytotoxic against HEI-OC1 cells, with an IC50 = 65.79  µM, compared to 611.7 µM for L-OHP and 882.9 µM for CBDCA, at the same molar concentration. The production of ROS was the most intense after CDDP, followed by L-OHP and CBDCA. In the comet assay, at the 100 µM concentration, L-OHP and CBDCA induced DNA adducts while CDDP induced adducts as well as DNA strand breaks. CBDCA and L-OHP lead to a significant increase of cleaved PARP at 24h (p < 0.001), suggesting an important apoptotic process induced by these compounds at the used concentrations. CONCLUSIONS: The results obtained in the current study suggest that the modulation of copper transporters locally may represent a new strategy against platinum drugs ototoxicity.

Comparative gonadotoxicity of the chemotherapy drugs cisplatin and carboplatin on prepubertal mouse gonads.

The treatment of childhood cancer with chemotherapy drugs can result in infertility in adulthood. Newer generations of drugs are developed to replace parent drugs, with the potential benefits of less toxic side effects. For platinum alkylating-like drugs, in contrast to the parent compound cisplatin, the newer-generation drug carboplatin is reported to have reduced toxicity in some respects, despite being administered at 5-15 times higher than the cisplatin dose. Whether carboplatin is also less toxic than cisplatin to the reproductive system is unknown. Here we compare the gonadotoxic impact of cisplatin and carboplatin on female and male mouse prepubertal gonads. In vitro cultured CD1 mouse ovaries or testis fragments were exposed to either cisplatin or carboplatin for 24 h on Day 2 of culture and analysed by Day 6. A dose response for each drug was determined for the ovary (0.5, 1 & 5 µg/ml cisplatin and 1, 5 & 10 µg/ml carboplatin) and the testis (0.01, 0.05 & 0.1 µg/ml cisplatin and 0.1, 0.5 & 1 µg/ml carboplatin). For the ovary, unhealthy follicles were evident from 1 µg/ml cisplatin (73% unhealthy, P = 0.001) and 5 µg/ml carboplatin (84% unhealthy, P = 0.001), with a concomitant reduction in follicle number (P = 0.001). For the testis, the proliferating germ cell population was significantly reduced from 0.05 µg/ml cisplatin (73% reduction, P = 0.001) and 0.5 µg/ml carboplatin (75% reduction, P = 0.001), with no significant impact on the Sertoli cell population. Overall, results from this in vitro animal model study indicate that, at patient equivalent concentrations, carboplatin is no less gonadotoxic than cisplatin.

Quantifying Drug-Induced Bone Marrow Toxicity Using a Novel Haematopoiesis Systems Pharmacology Model.

Haematological toxicity associated with cancer therapeutics is monitored by changes in blood cell count, and their primary effect is on proliferative progenitors in the bone marrow. Using observations in rat bone marrow and blood, we characterize a mathematical model that comprises cell proliferation and differentiation of the full haematopoietic phylogeny, with interacting feedback loops between lineages in homeostasis as well as following carboplatin exposure. We accurately predicted the temporal dynamics of several mature cell types related to carboplatin-induced bone marrow toxicity and identified novel insights into haematopoiesis. Our model confirms a significant degree of plasticity within bone marrow cells, with the number and type of both early progenitors and circulating cells affecting cell balance, via feedback mechanisms, through fate decisions of the multipotent progenitors. We also demonstrated cross-species translation of our predictions to patients, applying the same core model structure and considering differences in drug-dependent and physiology-dependent parameters.

Phase 1 study of veliparib (ABT-888), a poly (ADP-ribose) polymerase inhibitor, with carboplatin and paclitaxel in advanced solid malignancies.

PURPOSE: Veliparib is an oral inhibitor of poly (ADP-ribose) polymerase (PARP)-1 and -2. PARP-1 expression may be increased in cancer, and this increase confers resistance to cytotoxic agents. We aimed to determine the recommended phase 2 dose (RP2D), maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetics (PK) of veliparib combined with paclitaxel and carboplatin. METHODS: Eligibility criteria included patients with advanced solid tumors treated with ≤ 3 prior regimens. Paclitaxel and carboplatin were administered on day 3 of a 21-day cycle. Veliparib was given PO BID days 1-7, except for cycle 1 in the first 46 patients to serve as control for toxicity and PK. A standard "3 + 3" design started veliparib at 10 mg BID, paclitaxel at 150 mg/m2, and carboplatin AUC 6. The pharmacokinetic (PK) disposition of veliparib, paclitaxel, and carboplatin was determined by LC-MS/MS and AAS during cycles 1 and 2. RESULTS: Seventy-three patients were enrolled. Toxicities were as expected with carboplatin/paclitaxel chemotherapy, including neutropenia, thrombocytopenia, and peripheral neuropathy. DLTs were seen in two of seven evaluable patients at the maximum administered dose (MAD): veliparib 120 mg BID, paclitaxel 200 mg/m2, and carboplatin AUC 6 (febrile neutropenia, hyponatremia). The MTD and RP2D were determined to be veliparib 100 mg BID, paclitaxel 200 mg/m2, and carboplatin AUC 6. Median number of cycles of the three-agent combination was 4 (1-16). We observed 22 partial and 5 complete responses. Veliparib did not affect paclitaxel or carboplatin PK disposition. CONCLUSION: Veliparib, paclitaxel, and carboplatin were well tolerated and demonstrated promising antitumor activity.

Prevotella copri is associated with carboplatin-induced gut toxicity.

As a widely used cancer drug, carboplatin often results in serious side effects, such as gut toxicity. In this study, we examined the effects of gut microbiota on mice with carboplatin-induced intestinal mucosal damage. Carboplatin resulted in intestinal mucositis, as indicated by weight loss, diarrhoea, and infiltration of inflammatory cells. It markedly increased the expression of inflammatory cytokines/chemokines in intestine. Carboplatin also altered the diversity and composition of the gut microbiota. A significantly higher abundance of Prevotella copri (P. copri) was observed in carboplatin-treated mice. Moreover, the content of P. copri was positively correlated with the severity of intestinal mucositis. Pretreatment with metronidazole reduced the content of P. copri and relieved the intestinal mucosal injury and inflammation that was induced by carboplatin. Further study revealed that supplementation with P. copri in carboplatin-treated mice resulted in more severe tissue damage, lower tight junction protein expression and higher cytokine expression, and it enhanced both local and systemic immune responses. These data demonstrated that P. copri was involved in the pathological process of carboplatin-induced intestinal mucositis, suggesting a potential attenuation of carboplatin-induced intestinal mucositis by targeting P. copri.

Evaluation of mutagenic activity of platinum complexes in somatic cells of Drosophila melanogaster.

Cisplatin, carboplatin, and oxaliplatin are some of the most often used alkylating chemotherapeutic agents. In view of the paucity of data on the genotoxicity of oxaliplatin, this study compares the mutagenic activity of cisplatin (0.006, 0.012, 0.025, 0.05 mM), carboplatin (0.1, 0.2, 0,5, 1.0 mM), and oxaliplatin (0.1, 0.2, 0,5, 1.0 mM) using the somatic mutation and recombination test (SMART) in Drosophila melanogaster. Standard and high-bioactivation crosses of the drosophilid were used, which present basal and high levels of cytochrome P450 (CYP450) metabolization enzymes, respectively. All concentrations of cisplatin and carboplatin induced lesions in genetic material in both crosses, while oxaliplatin was mutagenic only to high bioactivation flies treated with 0.1, 0.5 and 1 mM of the compound. No significant differences were observed between genotoxicity values of cisplatin and carboplatin. However, CYP450 enzymes may have affected the mutagenic action of oxaliplatin. Carboplatin induced mainly mutation events, while cisplatin triggered mostly mutation and recombination events when low and high doses were used. Most events induced by oxaliplatin were generated by somatic recombination. Important differences were observed in genotoxic potential of platinum chemotherapeutic compounds, possibly due to the origin and type of the lesions induced in DNA and the repair mechanisms involved.

Harderian gland-derived stem cells as a cytotherapy in a guinea pig model of carboplatin-induced hearing loss.

BACKGROUND: Stem cells therapy of hearing loss is a challenging field due to lacking self-regenerative capacity of cochlea. Harderian gland of guinea pigs was thought to harbour a unique type of progenitors which could restore the damaged cochlear tissues. THE AIM: of this study was to isolate Harderian gland derived stem cells (HG-SCs) and investigate their efficacy in restoring the damaged cochlear tissue in carboplatin-induced hearing loss. METHODOLOGY: Sixty female and 10 male pigmented guinea pigs were used; the male animals were HG-SCs donors, while the females were assigned into 3 groups; control, hearing loss (HL) and HG-SC-treated groups. Auditory reflexes were assessed throughout the study. The animals were euthanized 35 days after HG-SCs transplantation, the cochleae were extracted and processed for assessment by light microscope and scanning electron microscope. Morphometric assessment of stria vascularis thickness, hair cells and spiral ganglia neuronal number and optical density of TLR4 expression were done. RESULTS: The isolated HG-SCs had the same morphological and phenotypical character as mesenchymal stem cells. HL group revealed destruction of organ of Corti, stria vascularis and spiral ganglion with decreased morphometric parameters. Restoration of both cochlear structure and function was observed in HG-SC-treated group along with a significant increase in IHCs, OHCs numbers, stria vascularis thickness and spiral ganglionic cell count to be close to the values of control group. CONCLUSION: The isolated HG-SCs were proved to restore structure and function of cochlea in guinea pig model of hearing loss.