Single Dose Of CDDP Research Articles

Multi-omics analysis reveals the protective effects of Chinese yam polysaccharide against cisplatin-induced renal interstitial fibrosis

BackgroundChinese yam polysaccharide (SYDT) has been reported to protect renal function and mitigate renal fibrosis in mice with diabetic nephropathy. Based on a multi-omics analysis, the objectives of this study were to determine the effect of SYDT on cisplatin (CDDP)-induced chronic renal interstitial fibrosis (RIF) and the underlying molecular mechanisms using an in vivo model. MethodsRats were intraperitoneally injected with a single dose of CDDP and then treated with SYDT or amifostine (AMF). The levels of urinary N-acetyl-β-D-glucosaminidase (NAG), blood urea nitrogen (BUN) and serum creatinine (Scr) were detected to assess renal function. Renal tissue damage and fibrosis were evaluated using hematoxylin and eosin (H&E) and Masson's trichrome staining, respectively. In addition, this study applied transcriptomics and metabolomics to predict the possible mechanism of SYDT action, which was verified by several relevant examinations. ResultsSYDT significantly protected the renal function, alleviated renal tissue damage and fibrosis, as well as decreased the protein levels of vimentin, α-SMA and CTGF, whereas SYDT significantly increased MMP-1 protein level in renal tissues from rats treated with CDDP. There were 1130 differently expressed genes (DEGs) between the CDDP model and SYDT-M groups proved by transcriptome analysis, indicating that metabolic pathways were likely the primary targets of relevance. Consistent with the transcriptome analysis, metabolome analysis identified 276 differentially expressed metabolites (DEMs) between the SYDT-M and CDDP model groups, with predominant clustering within glycerophospholipid metabolism. Integrative analysis of the transcriptome and metabolome indicated that SYDT inhibited the glycerophospholipid metabolism pathway by regulating the target genes Gpd2, Gpam, Agpat3, Lcat, and Pla2g4b. Notably, integrative analysis showed that the Phospholipase D (PLD) signaling pathway may be the most relevant target. Moreover, related signaling pathway analysis confirmed that SYDT inhibited CDDP-induced RIF in rats by down-regulating the PLD pathway. ConclusionOur study showed that the alleviation of CDDP-induced RIF in vivo can be achieved through the inhibition of glycerophospholipid metabolism and PLD signaling pathways by SYDT.

The ameliorative effect of Primula vulgaris on cisplatin-induced nephrotoxicity in rats and quantification of its phenolic components using LC-ESI-MS/MS

Cisplatin (CDDP) is an important chemotherapeutic agent, accumulation of which in kidney tissue causes nephrotoxicity and renal failure. The aim of this study was to evaluate, for the first time in the literature, the protective effect of dimethyl sulfoxide (DMSO) extract of Primula vulgaris leaf (PVE) against CDDP-induced nephrotoxicity in rats.The PVE content was characterized using liquid chromatography-mass spectrometry. Nephrotoxicity was induced with a single dose of CDDP (7.5 mg/kg). Thirty female Wistar-Albino rats were divided into five groups (control, DMSO, CDDP (7.5 mg/kg), CDDP + PVE (25 mg/kg), and CDDP + PVE (50 mg/kg)). Biochemical and histopathological analyses were then performed.Rutin, gallic acid, p-coumaric acid and protocatechuic acid were identified as major components of PVE. Total antioxidant status and glutathione (GSH) values increased significantly in the serum samples from the treatment group compared to the CDDP group, while blood urea nitrogen, creatinine, oxidative stress index, malondialdehyde (MDA), tumor necrosis factor-alpha (TNF-α), total oxidant status, and 8-hydroxy-2′-deoxyguanosine (8-OHdG) values decreased significantly. GSH levels increased significantly in the treatment group compared to the CDDP group, while TNF-α, caspase-3, 8-OHdG, MDA levels and damage scores decreased significantly.In conclusion, PVE exhibited strong protective effects through its anti-apoptotic, antioxidant, and anti-inflammatory activities against nephrotoxicity and oxidative damage caused by CDDP in rats.

Vanillic acid abrogates cisplatin-induced ovotoxicity through activating Nrf2 pathway

Although cisplatin (CDDP) is an effective anticancer agent, the ovotoxicity that can occur in female patients limits its use. Oxidative stress (OS) and inflammation are known to contribute to CDDP-induced ovotoxicity. Vanillic acid (VA) is a dietary herbal secondary metabolite with high free radical scavenging activity. It was aimed to evaluate the therapeutic effects of VA against CDDP-induced ovotoxicity in rats in this study for the first time. Ovotoxicity was achieved with a single dose of CDDP (5 mg/kg) in female rats. The therapeutic effect of VA was evaluated with 3-day administration of two different doses (5 and 10 mg/kg). While OS, inflammation, endoplasmic reticulum stress (ERS) and apoptosis markers were measured in tissue samples, the levels of reproductive hormones were determined in serum samples using colorimetric methods. The results showed that CDDP-induced nuclear factor erythroid 2-associated factor 2 (Nrf2) inhibition combined with increased OS, inflammation, ERS and apoptosis increased ovarian damage. VA treatments reversed these changes via activating Nrf2 pathway dose-dependently. In addition, histopathological findings also supported the biochemical results. VA may be a good therapeutic molecule candidate for CDDP-induced ovarian damage due to strong antioxidant and Nrf2 activator properties.

Eicosapentaenoic Acid Improves Cisplatin-Induced Muscle Atrophy Without Accompanying Body Weight Gain

Introduction: Cisplatin (CDDP) induces loss of muscle mass by activating the nuclear factor (NF)-κB signaling pathway. In this study, we investigated the effects of eicosapentaenoic acid (EPA), which inhibits NF-κB activation, on CDDP-induced loss of muscle mass in mice.Methods: Male C57BL/6J mice received a single dose of CDDP and olive oil, linseed oil, or EPA daily for 4 days. Body weight and food intake were recorded daily for 5 days. Forelimb grip strength was determined using a strain gauge on the fourth day. The mice were killed 24 h after the final dose of fatty acid and the wet weight of their gastrocnemius, soleus, and tibialis anterior muscles measured.Results: Olive oil, linseed oil, and EPA all failed to prevent decrease in food intake and loss of body weight. However, only EPA prevented loss of muscle mass and strength.Conclusion: EPA prevents CDDP-related loss of muscle mass and muscle but not CDDP-related loss of body weight.

Evaluation of the Effect of Pentoxifylline on Cisplatin-Induced Testicular Toxicity in Rats

Chemotherapy is associated with male infertility. Cisplatin (cis-diamminedichloro-platinum (II) (CDDP) as a chemotherapy medication used to treat a number of cancers has been reported to most likely induce testicular toxicity. Administration of antioxidants, such as pentoxifylline (PTX) may reduce some Adverse Drug Reactions (ADRs) of CDDR Therefore, this study investigated the potentially protective effects of PTX on CDDP-induced testicular toxicity in adult male rats. For this purpose, 42 male rats were randomly divided into 7 groups. The rats were orally preheated with PTX at the 3 doses of 75, 150, and 300 mg/kg once a day for 14 successive days. On the 14th day of the study, they were intraperitoneally (IP) administered with a single dose of CDDP (7 mg/kg). Finally, the sperm/testis parameters, serum levels of reproductive hormones, including testosterone, Luteinizing Hormone (LH), and Follicle Stimulating Hormone (FSH) as the pivotal endocrine factors controlling testicular functions, and histopathological changes of testis tissue were examined. Pretreatment with the two doses of 75 and 150 mg/kg PTX indicated significant increases in the sperm count and motility induced by CDDP administration. The right and significantly left testis weights were decreased following the treatment with 300 mg/kg of PTX plus CDDP. However, 75 mg/kg of PTX plus CDDP showed the best near-to-normal histopathological features. The results demonstrated that PTX alone enhanced some parameters, such as the sperm count, while reducing other parameters, including sperm fast motility and germ layer thickness. Furthermore, despite testosterone or LH levels, the mean serum FSH level was significantly augmented by the doses of 75 and 150 mg/ kg. It was concluded that PTX administration cannot reduce CDDP-induced testicular toxicity even at high doses (e.g., 300 mg/kg), while it seemed to partially intensify CDDP toxicity effects at a dose of 75 mg/kg. Thus, further research is required in this regard.

Age and Gender Related Renal Side Effects of Cisplatin in Animal Model

Backgrounds:Cisplatin (CDDP) is a choice of anti-cancer drug for cancer chemotherapy with serious side effects such as nephrotoxicity. It seems that age is an important factor influencing the side effects of CDDP. This study was designed to determine the role of age and gender simultaneously in CDDP induced renal toxicity.Methods:40 Wistar male and female rats were assigned as 6 groups in 3 different age categories (10, 16, and 20 weeks old). The single dose of CDDP (7.5 mg/kg, ip) was administrated, and a week later measurements were performed.Results:Body weight changes in male (not in female) animals aged 16 and 20 weeks were more than 10 weeks old animals (P<0.05). In male rats, the serum levels of creatinine (Cr) and blood urea nitrogen (BUN), and Cr-clearance in aged 10 weeks, normalized kidney weight (KW) in aged 20 weeks, and serum nitrite, aspartate aminotransferase (AST) and malondialdehyde (MDA) levels and kidney tissue damage score (KTDS) in rats aged 16 weeks were significantly altered (P<0.05). Gender difference in serum level of Cr, BUN and nitrite, and Cr-clearance were observed in animals aged10 weeks (P<0.05).Conclusion:The side effects of CDDP are gender depended, and may be different at various ages.

Effects of fennel essential oil on cisplatin-induced nephrotoxicity in ovariectomized rats

Background:Cisplatin (cis-diamminedichloroplatinum II (CDDP)) is an effective drug in cancer therapy to treat solid tumors. However, the drug is accompanied by nephrotoxicity. Previous reports indicated that estrogen has no protective role against CDDP-induced nephrotoxicity, but the role of phytoestrogen as an estrogenic agent in plants is not determined yet. The major composition of fennel essential oil (FEO) is trans-anethole that has estrogenic activity; so, we used FEO as a phytoestrogen source against CDDP-induced nephrotoxicity.Materials and Methods:Fifty-four ovariectomized Wistar rats were divided into seven groups. Groups 1-3 received different doses of FEO (250, 500, and 1000 mg/kg/day, respectively) for 10 days. Group 4 received saline for 10 days plus single dose of CDDP (7 mg/kg, intraperitoneally (ip)) at day 3. Groups 5-7 received FEO similar to groups 1-3, respectively; plus a single dose of CDDP (7 mg/kg, ip) on day 3. On day 10, the animals were sacrificed for histopathological studies.Results:The serum levels of blood urea nitrogen (BUN) and creatinine (Cr), kidney tissue damage score (KTDS), and kidney weight (KW) and body weight changes in CDDP-treated groups increased significantly (P < 0.05). FEO did not reduce the levels of BUN and Cr, KTDS, and KW and body weight changes. Also, the serum and tissue levels of nitrite were not altered significantly by FEO.Conclusion:FEO, as a source of phytoestrogen, did not induce kidney damage. In addition, FEO similar to estrogen was not a nephroprotectant agent against CDDP-induced nephrotoxicity.

Amelioration of cisplatin-induced rat renal lesions by a cyclooxygenase (COX)-2 selective inhibitor

Cyclooxygenase (COX)-2, an inducible form of COX, plays important roles in inflammatory lesions. We investigated effects of a COX-2 selective inhibitor, NS-398, on cisplatin (CDDP)-induced rat renal lesions. As compared with rats injected with a single dose of CDDP (6 mg/kg; CDDP group), rats who were treated everyday with NS-398 (3mg/kg) after the CDDP injection (inhibitor group), showed the declines of blood urea nitrogen and creatinine values, and the delay of the peak of regenerating renal epithelial cell number (demonstrable with 5'-bromo-2'-deoxyuridine immunohistochemistry); these findings suggested cytoprotective effects of the inhibitor. Furthermore, the numbers of ED1-immunopositive macrophages and α-smooth muscle actin (α-SMA)-immunopositive myofibroblasts were lower in the inhibitor group than in the CDDP group; mRNA expression of transforming growth factor-β1 (TGF-β1) was also decreased in the inhibitor group. Because the fibrotic area seen after CDDP injection were tended to decrease in the inhibitor group compared with the CDDP group, it was considered that the decreased number of infiltrating macrophages by the inhibitor might lead to the decreased production of TGF-β1, thereby resulting in the reduced number of α-SMA-positive myofibroblasts responsible for fibrosis. Collectively, although these differences between the CDDP and inhibitor groups were not always marked, the COX-2 inhibitor used in this study could ameliorate the CDDP-induced rat renal lesions.

Protective Effects of the Angiotensin II Receptor Blocker Losartan on Cisplatin-Induced Kidney Injury

Background: In the present study, we investigated the possible modulatory effect of losartan, an angiotensin receptor blocker, on oxidative stress induced by cisplatin (CDDP) as well as on CDDP uptake by the kidney. Methods: Rats were injected with a single dose of CDDP (7 mg/kg) and/or losartan (in either a single dose of 60 mg/kg or divided doses (10 mg/kg daily for 6 days), starting 1 h before CDDP injection. In addition, rat renal cortical slices were incubated with CDDP (2 mM) and/or losartan (2 mM) for 4 h. Nephrotoxicity was evaluated by measuring serum creatinine and blood urea nitrogen (BUN) in vivo and lactate dehydrogenase (LDH) leakage in vitro; histopathological examination of kidney tissue was also done. Oxidative stress markers including reduced glutathione (GSH) and lipid peroxides were also assessed. Furthermore, CDDP uptake by renal cortical slices was determined. Results: Losartan has protective effects against CDDP-induced nephrotoxicity as evidenced by restoration of normal serum levels of creatinine and BUN, and LDH leakage. Histopathological examination of the kidney confirmed these results. Also, losartan significantly counteracted CDDP-induced lipid peroxidation and GSH depletion. However, losartan did not affect CDDP uptake by the kidney. Conclusion: Our results indicate that losartan has proved to be a promising drug for clinical use as a nephroprotectant against CDDP-induced nephrotoxicity.

Propionyl‐L‐carnitine prevents The Progression of Cisplatin‐Induced Cardiomyopathy in a Carnitine‐Depleted Rat Model

This study is to investigate whether endogenous carnitine depletion and/or carnitine deficiency is a risk factor during development of cisplatin (CDDP)-induced cardiomyopathy and if so, whether carnitine supplementation by propionyl-L-carnitine (PLC) could offer protection against this toxicity. A total of 60 adult male rats were divided into 6 groups. The first three groups were injected intraperitoneally with normal saline, PLC (500 mg kg-1), and D-carnitine (500 mg kg-1) respectively, for 10 successive days. The 4th, 5th, and 6th groups were injected intraperitoneally with the same doses of normal saline, PLC and D-carnitine, respectively for 5 successive days before and after a single dose of CDDP (7 mg kg-1). Six days after CDDP treatment, animals were sacrificed, serum as well as hearts were isolated and analyzed. In the carnitine-depleted rat model, CDDP induced dramatic increase in serum cardiomyopathy enzymatic indices, CK-MB and LDH, as well as progressive reduction in total carnitine and ATP content in cardiac tissue. Interestingly, PLC supplementation attenuated CDDP-induced cardiomyopathy manifested by normalizing the increase of serum CK-MB and LDH, TBARS and NOx, and the decrease in total carnitine, GSH and ATP content in cardiac tissues. In conclusion, data from this study suggest for the first time that carnitine deficiency and oxidative stress are risk factors and should be viewed as mechanisms during development of CDDP-related cardiomyopathy and that carnitine supplementation, using PLC, prevents the progression of CDDP-induced cardiotoxicity.

Propionyl- l-carnitine prevents the progression of cisplatin-induced cardiomyopathy in a carnitine-depleted rat model

This study has been initiated to investigate whether endogenous carnitine depletion and/or carnitine deficiency is a risk factor during development of cisplatin (CDDP)-induced cardiomyopathy and if so, whether carnitine supplementation by propionyl- l-carnitine (PLC) could offer protection against this toxicity. To achieve the ultimate goal of this study, a total of 60 adult male Wistar albino rats were divided into six groups. The first three groups were injected intraperitoneally with normal saline, PLC (500 mg kg −1), and d-carnitine (500 mg kg −1) respectively, for 10 successive days. The 4th, 5th, and 6th groups were injected intraperitoneally with the same doses of normal saline, PLC and d-carnitine, respectively, for 5 successive days before and after a single dose of CDDP (7 mg kg −1). On day 6 after CDDP treatment, animals were sacrificed, serum as well as hearts were isolated and analyzed. CDDP resulted in a significant increase in serum creatine phosphokinase isoenzyme (CK-MB) and lactate dehydrogenase (LDH), thiobarbituric acid reactive substances (TBARS) and total nitrate/nitrite (NO( x)) and a significant decrease in reduced glutathione (GSH), total carnitine, and adenosine triphosphate (ATP) content in cardiac tissues. In the carnitine-depleted rat model, CDDP induced dramatic increase in serum cardiomyopathy enzymatic indices, CK-MB and LDH, as well as progressive reduction in total carnitine and ATP content in cardiac tissue. Interestingly, PLC supplementation resulted in a complete reversal of the increase in cardiac enzymes, TBARS and NO x , and the decrease in total carnitine, GSH and ATP, induced by CDDP, to the control values. Moreover, histopathological examination of cardiac tissues confirmed the biochemical data, where PLC prevents CDDP-induced cardiac degenerative changes while d-carnitine aggravated CDDP-induced cardiac tissue damage. In conclusion, data from this study suggest for the first time that carnitine deficiency and oxidative stress are risk factors and should be viewed as mechanisms during development of CDDP-related cardiomyopathy and that carnitine supplementation, using PLC, prevents the progression of CDDP-induced cardiotoxicity.

L-arginine ameliorates kidney function and urinary bladder sensitivity in experimentally-induced renal dysfunction in rats.

Effects of L-arginine and NG-nitro-L-arginine methyl ester (L-NAME) on the renal dysfunction that is induced by cisplatin (CDDP) were investigated. A single dose of CDDP (7.5 mg/kg i.p.) induced renotoxicity, which was manifested by increasing the sensitivity of isolated urinary bladder rings to acetylcholine (ACh), together with a significant elevation of serum urea and creatinine, and a severe decrease in serum albumin. Moreover, renal dysfunction was further confirmed by a significant decrease of enzyme activities, such as glutathione peroxidase, GSH-Px (E.C 1.11.1.9), catalase (E.C 1.11.1.6), as well as a significant increase in lipid peroxides that were measured as malondialdhyde (MDA) in kidney tissue homogenates. The administration of L-arginine (70 mg/kg/d p.o in drinking water 5 d before and 5 d after the CDDP injection) significantly ameliorated the renotoxic effects of CDDP, as judged by restoring the normal responses of isolated bladder rings to Ach, and also by an improvement in a range of renal function indices, which included serum urea and creatinine concentrations and kidney weight. In addition, L-arginine prevents the rise of MDA, as well as a reduction of GSH-Px and catalase activities in kidney tissues homogenates. On the other hand, the administration of L-NAME (4 mg/kg/d p.o) resulted in no protection against renal dysfunction that was induced by CDDP treatment. The findings of this study suggest that L-arginine can attenuate kidney injury that is produced by CDDP treatment. In addition, L-arginine may be a beneficial remedy for CDDP-induced renal toxicity, and could be used to improve the therapeutic index of CDDP.

Protective effect of aminoguanidine against nephrotoxicity induced by cisplatin in normal rats

The effect of aminoguanidine (AG) on nephrotoxicity induced by cisplatin (CDDP) was investigated. A single dose of CDDP (7.5 mg/kg i.p.) induced nephrotoxicity, manifested biochemically by a significant elevation in serum urea, creatinine and a severe decrease in serum albumin. Moreover, marked increases in kidney weight, urine volume and urinary excretion of albumin were observed. Nephrotoxicity was further confirmed by a significant decrease in glutathione- S-transferase (GST, E.C. 2.5.1.18), glutathione peroxidase (GSH-Px, E.C. 1.11.1.9) and catalase (E.C. 1.11.1.6) and a significant increase in lipid peroxides measured as malondialdhyde (MDA) in kidney homogenates. Administration of AG (100 mg/kg per day p.o.) in drinking water 5 days before and 5 days after CDDP injection produced a significant protection against nephrotoxicity induced by CDDP. The amelioration of nephrotoxicity was evidenced by significant reductions in serum urea and creatinine concentrations. In addition, AG tended to normalize decreased levels of serum albumin. Urine volume, urinary excretions of albumin and GST and kidney weight were significantly decreased. Moreover, AG prevented the rise of MDA and the reduction of GST and GSH-Px activities in the kidney. These results suggest that AG has a protective effect on nephrotoxicity induced by CDDP and it may therefore improve the therapeutic index of CDDP.

Pharmacological Modulation of Cisplatin Toxicity Rhythms with Buthionine Sulfoximine in Mice Bearing Pancreatic Adenocarcinoma (PO3)

In a previous report, we showed that the circadian rhythm of cisplatin (cis-diamminedichloroplatinum, CDDP) toxicity in healthy mice was modified by buthionine sulfoximine (BSO), a specific inhibitor of glutathione (GSH) synthesis. In the present study, the effects of BSO on the rhythms of CDDP toxicity and antitumor efficacy were investigated in mice bearing a transplantable pancreatic adenocarcinoma (PO3). B6D2F1 mice were inoculated widi two 4 mm3 tumor fragments, one in each flank, then were synchronized with an alternation of 12h of light (L) and 12h of darkness (D) (LD 12: 12). Three weeks later, a single dose of CDDP (12 mg/kg iv) was injected at 3h, 7h, 11h, 15h, 19h, or 23h after light onset (HALO) with or without prior BSO (450 mg/kg ip 4h earlier). The antitumor activity of CDDP as assessed by tumor weight change and tumor growth delay was weak in this tumor model irrespective of prior BSO administration or CDDP dosing time. Nevertheless, toxic effects of CDDP as gauged by body weight loss or survival varied significantly according to CDDP dosing time. Body weight loss was least in mice receiving CDDP alone at the mid-to-late active span. Survival rate was 97% in mice treated with CDDP alone and 47% in those receiving prior BSO (χ2 = 23.6, p <. 0001). BSO pretreatment further shifted the period of survival or body weight change from 24h to (10 + 24)h, an effect similar to that earlier reported in healthy mice. Thus, PO3 tumor at a measurable stage altered neither the circadian rhythm in CDDP toxicity nor the ultradian rhythm in the toxicity of BSO-CDDP combination. The results suggest that rhythms in target tissues for drug actions can be manipulated with biochemical modulators, thus partly escaping central clock control.

Effect of cisplatin on the basement membrane anionic sites in the ampulla, macula, and stria vascularis of guinea pigs.

Our objective was to compare changes in the basement membrane anionic sites (BMAs) in the ampulla, macula, and stria vascularis following the infusion of cisplatin (CDDP). After CDDP was administered to anesthetized Hartley guinea pigs, the bony labyrinth was immersed in a solution of polyethyleneimine (PEI). The size and distribution of PEI particles associated with BMAs in the stria vascularis and in the dark cell and sensory cell areas of the vestibular labyrinth were determined by electron microscopy. A significant reduction in the number and size of PEI particles was observed on CDDP-treated strial vessels. The number and size of PEI particles on the basement membranes of the vestibular labyrinth did not differ from those in the control. Our findings suggest that the BMAs of the vestibular labyrinth were not significantly affected by the administration of a single dose of CDDP.

A study on the relationship between sensitivity to CDDP and inducibility of metallothionein and glutathione of genitourinary tumors

In this paper we demonstrate the relationship between the antitumor activity of cis-diamminedichloroplatinum (II) (CDDP) and inducibility of metallothionein (MT) and glutathione (GSH) of genitourinary tumors. The chemosensitivity test was performed in athymic mice bearing tumors derived from the human tumor cell lines: ACHN (renal cell carcinoma), NMB-1 (urinary bladder transitional cell carcinoma), and NMT-1 (testicular embryonal cell carcinoma). A single dose of CDDP (25 mumol/kg body weight), was administered i.p. to athymic tumor bearing mice. Concentrations of platinum, MT, and GSH were measured in organ and tumor homogenates 24 h after CDDP administration. We observed that tumors derived from NMB-1 and NMT-1 were very sensitive to CDDP, but ACHN derived tumors were resistant to CDDP. Measurement of platinum concentrations in tumor tissues revealed no correlation to the observed chemosensitivities of the tumors. Furthermore, 24 h after CDDP administration, the levels of MT and GSH in NMB-1 and NMT-1 derived tumors were lower them or equal to those of control mice. In contrast, mice bearing tumors derived from ACHN exhibited a 1.7-fold and a 2.1-fold increase in MT and GSH, respectively, as compared to control mice. These findings suggest that the inducibility of MT and GSH in tumor tissues following CDDP administration may be a contributing factor in the development of CDDP resistance in renal cell carcinoma.

Pharmacokinetics and tissue distribution of cisplatin in nude mice: platinum levels and cisplatin-DNA adducts.

The pharmacokinetics of platinum (Pt) and cisplatin (CDDP)-DNA adducts were studied in nude mice after single-dose CDDP treatments. Whole blood, serum, kidney, lever, testis, brain, and tumor were collected at different intervals after injection of CDP at different dose levels. Pt was measured with flameless atomic absorption spectrometry (FAAS) or adsorptive voltammetry (AdV) and CDDP-DNA adducts with quantitative immunohistochemistry. The drug was immediately absorbed into the blood circulation (peak serum Pt levels were reached within 5 min) after i.p. CDDP administration, and distribution into most tissues also occurred rapidly (tissue Pt levels peaked at 15 min). With a sampling period of 7 days there was a biphasic elimination of Pt from blood, serum, and tissues. In the brain the pharmacokinetics differed with a gradual accumulation of Pt occurring during the 1st week. Formation of CDDP-DNA adducts in tissues was a slower process, with maximal levels being achieved at between 30 min and 4 h after drug administration, followed by a steady state lasting for at least 24 h. Each tissue type had its specific immunohistochemical staining pattern of adducts. With escalating CDDP doses there was a linear, or almost linear, increase in Pt concentrations and CDDP-DNA adduct levels in all sample types examined. These results suggest that a fair estimation of the amount of drug in tumor and normal tissues can be made from analysis of serum Pt at a fixed time point after a single dose of CDDP.

The influence of cisplatin on the response of mouse kidneys to multifraction irradiation

The aim of these studies was to measure the extent of renal damage after fractionated irradiation in combination with cis-diamminedichloroplatinum(II) (c-DDP) and to determine whether there was any drug-induced inhibition of repair of sublethal X-ray damage. Fractionated irradiations were given either in a short overall treatment time of 2 days or in a total time of one month, in which irradiations were given in the first and fourth weeks only. A single dose of c-DDP was given before the first X-ray dose for treatments in a total time of 2 days and before the first X-ray dose of each week for the split-course treatments. Renal function was measured at monthly intervals (from 18 to 39 weeks after the start of treatment) by clearance of 51Cr-EDTA. The renal damage was always worse after combined treatments (X + c-DDP) than after X-rays alone. A comparison of radiation dose-response curves with and without c-DDP yielded Dose Enhancement Factors (DEFs) of 1.2 to 1.4 for all fractionation schedules, with no trend for an increase in DEF with increasing number of fractions. A Linear-Quadratic (LQ) analysis of the data demonstrated that there was no change in the α/β value for renal radiation damage for the combined treatments compared with X-rays alone (α/β = 2–3 Gy). These results suggest that the increased renal damage which occurred after combined X + c-DDP was due to independent, additive toxicities and not to radiosensitization or inhibition of X-ray repair by the drug.

Potentiation of combination effect of cisplatin and radiation--application of biological response modifiers

The combination antitumor effect of three kinds of biological response modifiers (lentinan, PSK and juzentaiho-to) was evaluated in the treatment of IMC solid carcinoma with CDDP (9 mg/kg) and/or radiation (1000 rad). Remarkable antitumor effects were observed in the lentinan (2 mg/kg, daily) group to which a single dose of CDDP was given 24 hours before irradiation. On the other hand, combined therapy with CDDP and radiation alone showed less antitumor effect. No antitumor effect was observed in the groups treated with biological response modifiers (BRM) alone. Winn's test was performed to investigate the level of immunity on each treatment group. Mice were inoculated with the admixtures of immunized spleen cells and IMC carcinoma cells at a ratio of 200:1. Tumor growth was completely suppressed in the groups of CDDP and lentinan with or without radiation even on the 41st day after inoculation. These results are strongly suggestive of potentiation of the immunity of tumor bearing mouse by the combined use of lentinan. Histopathological evaluation also revealed a potent antitumor effect of combined use of lentinan. Since host immunity is known to be suppressed in the tumor bearing state, combined use of BRM in chemo-radiotherapy must play an important role in the treatment of malignant tumor.