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In 2010, the combination of cisplatin + gemcitabine (CISGEM) showed its -superiority over gemcitabine alone in first-line treatment of advanced biliary tract cancers (BTC) in the ABC-02 trial. For more than 10 years, no study then showed a benefit in intensifying chemotherapy or combining targeted therapy with CISGEM. Recently, a step was finally taken with the demonstration of the benefit provided by the addition of an immunotherapy to CISGEM, first durvalumab in the TOPAZ-1 study (the new standard of care in first-line) then pembrolizumab in the KEYNOTE-966 trial. BTC contain frequent molecular alterations whose therapeutic targeting has already been demonstrated to be effective in 2nd line or higher and could also be interesting in the first line in the future. [ABSTRACT FROM AUTHOR]

Roughly 20% of patients with non-small-cell lung cancer exhibit locally advanced, unresectable, stage III disease. Concurrent platinum-based chemoradiotherapy is the backbone treatment, which is followed by maintenance immunotherapy, yet with poor long-term prognosis. This phase II trial (IFCT-0803) sought to evaluate whether adding cetuximab to cisplatin and pemetrexed chemoradiotherapy would improve its efficacy in these patients. Eligible patients received weekly cetuximab (loading dose 400 mg/m2 day 1; subsequent weekly 250 mg/m2 doses until two weeks postradiotherapy). Chemotherapy comprised cisplatin (75 mg/m2) and pemetrexed (500 mg/m2), both delivered on day 1 of a 21-day cycle of maximally four. Irradiation with maximally 66 Gy started on day 22. Disease control rate at week 16 was the primary endpoint. One hundred and six patients were included (99 eligible patients). Compliance exceeded 95% for day 1 of chemotherapy cycles 1 to 4, with 76% patients receiving the 12 planned cetuximab doses. Maximal grade 3 toxicity occurred in 63% patients, and maximal grade 4 in 9.6%. The primary endpoint involving the first 95 eligible patients comprised two (2.1%) complete responses, 57 (60.0%) partial responses, and 27 (28.4%) stable diseases. This 90.5% disease control rate (95% confidence interval [95% CI]: 84.6%–96.4%) was achieved at week 16. After median 63.0-month follow-up, one-year and two-year survival rates were 75.8% and 59.5%. Median overall survival was 35.8 months (95% CI: 23.5–NR), and median progression-free survival 14.4 months (95% CI: 11.2–18.8), with one-year and two-year progression-free survival rates of 57.6% and 34.3%. These survival rates compare favourably with published data, thus justifying further development of cetuximab-based induction chemoradiotherapy. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to investigate the protective activity of brown seaweed, the ethanolic and water extracts of Sargassum binderi (S. binderi) were examined. Anticancer drug, cisplatin is normally used for the treatment of solid tumors that cause acute kidney damage after assemblage in the renal tubules., Material and Methods: It was an acute nephrotoxicity study, animals were divided into several groups randomly, cisplatin (7mg/kg i.p.) and normal saline were used as positive and negative control respectively. The S. bindari ethanolic and water extract were given orally in a dose of 200mg/kg for 5days. Various biomarkers were assessed to observe the nephroprotective potential, while antioxidant activities were investigated using reduced glutathione, catalase and malondialdehyde as oxidative stress. GCMS was performed to validate the presence of important therapeutic moieties., Results: The current result justified that pretreatment with S. binderi inhibited the elevation of antioxidant parameters and also showed protection against lipid peroxidation, induced by cisplatin challenge. The overall impact was the nephroprotection, which has been revealed from the results. GCMS evaluation of hexanes fraction revealed the presence of therapeutically important compounds including heptasiloxane, 3,7,11,15-tetramethyl-2-hexadecen-1-ol, hexadecamethyl, cyclooctasiloxane, and hexadecamethyl. These compounds have been reported for their antioxidant, antibacterial, anticancer, and antifungal activities., Conclusion: S. binderi showed reno-protective effect by checking their well-known biochemical parameters probably due to the antioxidant activity as confirmed by the presence of compounds., (Copyright © 2024 Académie Nationale de Pharmacie. Published by Elsevier Masson SAS. All rights reserved.)

Chemoradiotherapy with concurrent cisplatin has been the standard treatment for locally advanced head and neck squamous cell carcinoma (HNSCC) for over 20 years. Recently, immunotherapy, a new therapeutic class, has emerged for patients with recurrent or metastatic HNSCC and has significantly extended their survival. Will it bring the same benefit to patients with localized tumors? There is a strong rationale for combining radiation therapy and checkpoint inhibitors for HNSCC. Indeed, radiation therapy can have both immunostimulatory and immunomodulatory effects. This is what explains the famous abscopal effect. The aim of this review is to present the data available on the combination of radiation therapy and immunotherapy for HNSCC. [ABSTRACT FROM AUTHOR]

La tolérance rénale des anticancéreux est un problème lié à la fois à la toxicité intrinsèque de certaines chimiothérapies anticancéreuses et au terrain représenté par le patient cancéreux lui-même. Le patient atteint de cancer est, en effet, exposé à tous les types d'atteinte rénale (obstructive, fonctionnelle, organique secondaire aux traitements, à la radiothérapie, à une glomérulopathie paranéoplasique, à une microangiopathie thrombotique, etc.). L'indice thérapeutique des anticancéreux est souvent faible et les doses prescrites élevées pour obtenir une efficacité optimale sur la cellule cancéreuse. L'amélioration de la tolérance passe par la meilleure adaptation des doses, elle-même conditionnée par l'évaluation correcte de la fonction rénale. La prévention reste indispensable, d'autant que la mortalité associée à l'insuffisance rénale aiguë est très élevée. The renal toxicity of anticancer drugs is a clinical challenge because of the intrinsic toxicity of some anticancer drugs and because the cancer itself. Indeed, cancer patients are exposed to all types of renal disorders (obstructive, functional, organic because of radiotherapy, paraneoplastic glomerulopathy, thrombotic microangiopathy...). The therapeutic index of anticancer drugs is often narrow and the doses used for optimal efficacy are high. Improving safety requires a better dose adjustment, which depends on the correct evaluation of the renal function. Prevention remains important as the mortality associated with acute renal failure is very high. [ABSTRACT FROM AUTHOR]

Chemoradiotherapy is now considered the standard of care for many locally advanced diseases. Cytotoxic drugs have been largely evaluated in this setting, with cisplatin and 5FU the most often used drugs. A large amount of pre-clinical studies has demonstrated the synergy between both modalities. Concomitant administration seems the more beneficial in many diseases. Emergence of new approaches, combining targeted therapies and radiotherapy (RT) is now a reality. The main example is the association of cetuximab and RT in head and neck carcinomas, even if, 14 years after the initial publication, the best way to use it is still unknown. New compounds as inhibitors of DNA-repair or immune checkpoints are under investigation and showed early promising results. [ABSTRACT FROM AUTHOR]

Le carcinome épidermoïde cutané (CEC) représente la seconde tumeur cutanée en termes de fréquence. Même si un traitement chirurgical guérit la grande majorité des CEC, certaines tumeurs évoluées localement ou métastatiques nécessitent d'autres approches thérapeutiques. La chimiothérapie avec des sels de platine a une efficacité, mais son administration est souvent limitée par la survenue de toxicité, en particulier chez les sujets âgés. Les anti-EGFR peuvent également avoir une activité souvent limitée dans le temps. En raison essentiellement d'une charge tumorale élevée et de l'expression de PD-L1 dans les CEC évolués, il existe un fort rationnel pour l'utilisation des nouvelles immunothérapies. Un essai précoce de phase 1b avec le REGN2810 chez des patients prétraités montre un taux de réponse de 46 %, ouvrant la porte au développement des inhibiteurs de l'axe PD-1/PD-L1 dans cette indication. [ABSTRACT FROM AUTHOR]

PRPS1 (phosphoribosyl pyrophosphate synthetase 1), which drives the nucleotide biosynthesis pathway, modulates a variety of functions by providing central building blocks and cofactors for cell homeostasis. As tumor cells often display abnormal nucleotide metabolism, dysregulated de-novo nucleotide synthesis has potential impacts in cancers. We now report that PRPS1 is specifically and highly expressed in chemoresistant (CR) cancer cells derived from cisplatin-resistant human breast cancer cell lines SK-BR-3 and MCF-7. The inhibition of PRPS1 activity in CR cells by genetic silencing reduces cell viability and increases apoptosis in vitro, both of which can be further potentiated by cisplatin treatment. Significantly, such down-regulation of PRPS1 in CR cells when administered to nude mice enhanced the survival of those animals, as demonstrated by decreased tumor growth. Knockdown of PRPSI may cause these effects by potently inducing autonomous activation of caspase-3 and inhibiting the proliferation in the engrafted CR tumors. As a result, cisplatin sensitivity in a xenograft model of CR cancer cells can be restored by the down-regulation of PRPS1. Thus, PRPS1 inhibition may afford a therapeutic approach to relapsed patients with breast cancer, resistant to chemotherapy. [ABSTRACT FROM AUTHOR]

Systems containing platinum (Pt) are more challenging for reliable computations, because Pt has 78 electrons and requires relativistic treatment. However, to reduce computational demands, most previous researchers used effective core potentials. In this investigation, we perform numerous computations on the cisplatin molecule with ab initio methods and density functional theory, some of which involve all electron and zero-order relativistic approximation. Tentative conclusions on the reliability of various methods are drawn from comparison of our results with previous calculations and available experimental data. Vibrational and electronic spectra are calculated and compared with previous studies and available experimental data. [ABSTRACT FROM AUTHOR]

Nephrotoxicity is a dose-limiting side effect of cisplatin (CSP). The study investigated the possible protective role of trimetazidine (TMZ) against CSP-induced nephrotoxicity in rats. Rats were divided into four groups; control, TMZ, CSP, and CSP + TMZ. The CSP group showed significant deterioration in kidney function with structural changes in the form of interstitial hemorrhage, glomeruli shrinkage and peritublar capillary congestion, tubular cells vacuolation, pyknosis, shedding and necrosis, and inflammatory cell infiltrates, all indicating renal damage. CSP also caused a significant increase in the lipid peroxidation marker malondialdehyde (MDA) levels, renal nuclear factor kappa B (NF-κB) DNA-binding activity and protein expression, and tumor necrosis factor alpha (TNF-α) and IL-6 levels. Treatment with TMZ before and after CSP injection produced significant improvement of kidney function and histopathology. TMZ treatment also significantly attenuated CSP-induced oxidative stress and suppressed elevated levels of TNF-α and IL-6 and NF-κB expression and its DNA-binding activity caused by CSP administration. TMZ has a protective effect against CSP-induced nephrotoxicity mediated by reduction of oxidative stress and attenuation of CSP-induced inflammation. [ABSTRACT FROM AUTHOR]

This study was designed to evaluate the protective effects of trimetazidine (TMZ) against cisplatin (CP) induced liver damage in rats. Animals were distributed among 4 groups as follows: control group; TMZ group (20 mg/kg body mass, per oral), which was treated for 10 days; CP group (6 mg/kg, by intraperitoneal injection), which received a single injection; and the CP + TMZ group (20 mg/kg, per oral), which received TMZ 4 days before and 6 days after CP injection. The extent of hepatic damage was studied by assessing biochemical parameters and histopathological evaluation of the extracted liver tissue. The results revealed that liver enzymes were markedly elevated after injection of CP, as evident from significant increases in the serum levels of alanine transaminase (AST), alanine aminotransferase (ALT), gamma glutamyl transferase (γ-GT), and lactate dehydrogenase (LDH), as well as marked changes to the liver architecture, with a significant decrease in serum levels of albumin. There were also marked changes to the antioxidant defense system, as indicated by significant decreases in total antioxidants and hepatic levels of reduced glutathione (GSH) and superoxide dismutase (SOD), together with a significant increase in lipid peroxidation. However, there was a significant increase in the activity of hepatic nuclear factor kappa B (NF-κB) as well as hepatic Bax protein expression. We conclude that TMZ protects against CP-induced liver damage through scavenging free radicals and anti-inflammatory and antiapoptotic effects, as well as through reducing NF-κB activation. [ABSTRACT FROM AUTHOR]

This study investigated the preventive role of resveratrol in cisplatin-induced nephrotoxicity. The study used groups of New Zealand rabbits that were treated as follows: group C (cisplatin treated), group R (resveratrol treated), group R+C (resveratrol + cisplatin treatment), and group E (control group). Kidney levels of glutathione were significantly lower in group C than in groups E and R, whereas glutathione levels in group R+C were found to be similar to the control values. Malondialdehyde levels in group C were significantly higher than in groups E and R. However, malondialdehyde levels in group R+C were similar to group E. Kidney levels of nitric oxide were significantly higher in the cisplatin group than in the control, whereas nitric oxide levels were at basal values in group R+C. Cisplatin treatment significantly reduced kidney levels of glutathione peroxidase, superoxide dismutase, and catalase activity compared with those of group E, whereas resveratrol treatment significantly increased levels of glutathione peroxidase, superoxide dismutase, and catalase activity in group R+C. However, cisplatin injection did not affect mRNA levels of glutathione peroxidase, superoxide dismutase, or catalase enzymes. Histopathological and immunohistochemical analyses indicated that cisplatin caused kidney damage, which was mostly prevented by resveratrol treatment. In conclusion, resveratrol ameliorates cisplatin-induced oxidative injury in the kidney of rabbit. [ABSTRACT FROM AUTHOR]

Résumé Le traitement systémique des malades atteints d’un cancer bronchique avec métastases cérébrales est guidé par les caractéristiques cliniques (présence de symptômes), histologiques et biologiques de la maladie. L’efficacité de la chimiothérapie standard (basée sur un sel de platine) est comparable dans l’encéphale et en dehors, et justifie son utilisation en première ligne thérapeutique. L’efficacité des traitements bioguidés (inhibiteurs de tyrosine kinase de l’ epidermal growth factor receptor [EGFR], de l’ anaplastic lymphoma kinase [ALK]) dans l’encéphale est démontrée, est supérieure à celle de la chimiothérapie standard et justifie leur utilisation en première ligne thérapeutique en cas de mutation tumorale activatrice de l’EGFR ou de réarrangement de l’ALK (dès que la modification d’autorisation de mise sur le marché [AMM] du crizotinib sera obtenue en France). L’utilisation concomitante de la radiothérapie panencéphalique et d’un traitement systémique (chimiothérapie et thérapies ciblées) n’est pas recommandée en l’absence de données concernant une amélioration éventuelle de l’efficacité et/ou de tolérance. Plusieurs essais sont en cours pour évaluer de nouvelles modalités de radiothérapie panencéphalique, de nouvelles monothérapies ciblées ou combinaisons, incluant en particulier l’immunothérapie. Systemic treatment of lung cancer patients with brain metastases is based on clinical (presence of symptomatic intracranial lesions), pathological and molecular characteristics of the disease. The efficacy of standard platinum-based chemotherapy is comparable inside and outside the brain, justifying its use as front-line therapy. The intracranial efficacy of targeted therapies (EGFR tyrosine kinase inhibitors, ALK inhibitors) is demonstrated, and is globally superior to the efficacy of standard chemotherapy, justifying their use as front-line therapy in case of EGFR activating mutation or ALK rearrangement (providing the change in the crizotinib label in France). The concomitant use of whole brain radiotherapy and a systemic treatment (chemotherapy or targeted therapy) is not recommended in the absence of a demonstrated better efficacy and/or acceptable safety profile. Several trials are ongoing to assess new whole brain radiotherapy modalities, new targeted therapies alone or in combination, especially exploring immunotherapy. [ABSTRACT FROM AUTHOR]

Aberrant activation of Wnt/β-catenin induces renal dysfunction by initiating pro-apoptotic cascades, fibrosis, oxidative and inflammatory burden. This study tested the therapeutic effects of Wnt/β-catenin inhibitor pyrvinium against cisplatin-induced acute kidney injury (AKI) in rats. Cisplatin was administered at a single dose of 5 mg/kg (i.p.) and renal cisplatin accumulation and uptake in cortical slices were determined after the fifth day by atomic absorption spectroscopy. Levels of pro-inflammatory cytokines were checked by ELISA, and organic cation transporter-2 (OCT-2) transcription and expression in renal tissue were evaluated by RT-PCR and immunohistochemical technique. Cisplatin administration produced renal dysfunction manifested as increase in serum creatinine, blood urea nitrogen, proteinuria, reduced clearance and electrolyte imbalance. Oxidative stress indices, pro-inflammatory cytokines, fibronectin, and caspase-3 activity were elevated in cisplatin-challenged rats. Moreover, increased renal OCT-2 transcription and immunostaining were detected in cisplatin kidneys which resulted in platinum accumulation. Additional docking studies depicted strong interaction between the β-catenin and OCT-2 protein. These manifestations induced mitochondrial dysfunction, histological damage and fibrosis. Notably, Wnt/β-catenin inhibitor pyrvinium (60 µg/kg; p.o.) treatment reduced the renal OCT-2 gene transcription causing a decline in platinum levels. Thus, the present study concludes that Wnt/β-catenin inhibition attenuates cisplatin-induced AKI in rats, partly by down-regulating OCT-2 expression.

Primary therapy for high-risk gestational trophoblastic neoplasia (GTN) includes a multi-agent, methotrexate-based regimen, named EMA/CO. In France, the guidelines recommend the use of either a platinum-based protocol when methotrexate is contra-indicated or a highdose EMA/CO once brain metastases are diagnosed. For patients who are resistant to the initial therapy, different salvage approaches have been developed or adapted from treatments already used for germ cell tumors. Currently, the most frequently used protocol is a combination of etoposide and platinum-based therapy (EMA/EP). In the EMA/EP protocol, etoposide and cisplatin are used in place of cyclophosphamide and vincristine (CO in the EMA/CO regimen) with the goal of reversing resistance mechanisms of previously used drugs. Although, new approaches for improving the management of high-risk patients who are resistant or refractory to the initial therapy are now available, new molecules are still awaited to optimize patient's care. [ABSTRACT FROM AUTHOR]

Testicular tumours are the most common form of cancer in young men. Since the 1970s, metastatic germ cell tumours have become the curable cancer paradigm through the use of cisplatin-based chemotherapy and surgical removal of the residual mass. The prognosis for patients is defined using the International IGCCCG classification, which enables the appropriate amount of chemotherapy therapy to be administered in order to achieve recovery. In the most serious forms, early adaptation of the chemotherapy regimen based on the decreasing levels of serum markers has been shown to be effective. Despite these treatments, approximately 20% of patients relapse and require a second line treatment, either at a standard dose or at an intensified level with a stem cell transplant. Follow-up of patients in complete remission is important, not only for the early detection of any relapses, but also to screen for testicular cancer in the other side, associated with the potential desire to father a child, and favours the best possible social rehabilitation of the patient. [ABSTRACT FROM AUTHOR]

Irinotecan and cisplatin are two chemotherapeutic agents whose frequent and serious adverse effects - haematological and gastrointestinal toxicity for irinotecan, ototoxicity for cisplatine - show wide and partly genetic-based interindividual variability. Several studies have been undertaken to identify genetic variants responsible of these toxicities in order to predict the risk for patients to suffer from them and to adapt treatment to risk levels. Concerning irinotecan, dosing recommendations are about to emerge from many UDP-glucuronosyl-transferase 1A1 (UGT1A1, main enzyme inactivating the active metabolite of irinotecan SN-38) polymorphism-related studies. The development of such recommendations may be complicated by the recent discovery of the role of other enzymes (from the same UGT1A subfamily) and carriers (particularly ATP-binding cassette (ABC) superfamily) involved in irinotecan's pharmacokinetics. For cisplatin, identifying candidate genes is still ongoing because of controversies about different studies' results. Several genes involved in intracellular processes of ototoxicity were discussed, such as the Glutathione S-transferases (GST), megalin, thiopurine methyltransferase (TPMT), catechol O-methyltransferase (COMT) and ABCC3 genes. The last three genes have recently been incorporated in a predictive model of ototoxicity. For both drugs, further studies are still needed to reach a complete individualization of treatment. [ABSTRACT FROM AUTHOR]

The chemotherapeutic agent cisplatin accumulates in the kidney and induces acute kidney injury (AKI). Preclinical and clinical studies suggest that young female mice and women show greater recovery from cisplatin-AKI compared to young male mice and men. The endothelin (ET) and ET receptors are enriched in the kidney and may be dysfunctional in cisplatin-AKI; however, there is a gap in our knowledge about the putative effects of sex and cisplatin on the renal ET system. We hypothesized that cisplatin-AKI male and female mice will have increased expression of the renal ET system. As expected, all cisplatin-AKI mice had kidney damage and body weight loss greater than control mice. Cisplatin-AKI mice had greater cortical Edn1, Edn3, Ednra , and Ednrb , while outer medullary Ednra was significantly suppressed in both sexes. Of the ∼25 000 genes sequenced from the inner medulla, only 91 genes (comparing saline mice) and 134 genes (comparing cisplatin-AKI mice) were differentially expressed and they were unrelated to the ET system. However, Edn1 was significantly greater in the inner medulla of male and female cisplatin-AKI mice. Thus, RNA profiles of the ET system were significantly affected by cisplatin-AKI throughout the kidney regardless of sex and this may help determine the therapeutic potential of targeting the ET receptors in cisplatin-AKI.

Chemotherapy is one of the most important strategies in the treatment of cancer; however, chemoresistance restricts the effect of chemotherapy. Growing reports suggest that chloride channel-3 (ClC-3) is involved in regulating the sensitivity of multiple chemotherapeutic agents in the chemotherapy of various tumours, while its role in the chemotherapy of cholangiocarcinoma (CCA) is still poorly understood. Herein, we observed that ClC-3 was highly expressed in CCA chemoresistant tissues and CCA cisplatin-resistant cells QBC939/DDP, and the sensitivities of QBC939 and QBC939/DDP cells to cisplatin were all increased after inhibition of ClC-3. Further mechanism exploration revealed that ClC-3 knockdown reduced the level of autophagy. Furthermore, in both QBC939 and QBC939/DDP cells, the autophagy agonist rapamycin eliminated the increased cisplatin sensitivity of ClC-3 knockdown without affecting ClC-3 expression. Collectively, all the findings demonstrate that ClC-3 knockdown increases cisplatin-induced cell death in CCA cells though inhibiting autophagy, regardless of the occurrence of cisplatin resistance. In addition, our results also suggest that targeted inhibition of ClC-3 may be a potential strategy for chemosensitization in CCA chemotherapy.

The article discusses the results of a study that investigates the antioxidant effects of a grape seed extract (GSE) in three groups of male rabbits that are treated with cisplatin in New Zealand. It examines the histopathological findings of severe necrosis, mononuclear infiltration and hepatocyte degeneration in the liver that is associated with the accumulation of malondialdehyde and increase of serum activities. It offers information on the attenuation of liver injury that is mediated with cisplatin.

The article offers information on a study to evaluate the efficiency of human genital organ tumor drugs, cisplatin and doxorubicin for the treatment of transmissible venereal tumors (TVT) in bitches that have normocytic-hypochromic anemia and leucocytosis. It discusses the regression of the TVT in the group of bitches treated with doxorubicin for five times that have 21 interval days. It examines the deaths of six animals during the cisplatin treatment, although regression is evident in the remaining animals on their third treatment.

Background: The concurrent chemoradiotherapy for cervical cancer treatment is well accepted since 1999. This randomized, phase III trial aimed to observe if any improved outcome could be obtained capitalizing on the synergistic activity of gemcitabine, cisplatin, XRT. Materials and Methods: Stage IIB-IIIB, 18-70 years of age, KPS score ≥70, were randomized to control group and study group. Control group received cisplatin 40 mg/m2 weekly with concurrent XRT, followed by brachytherapy and study group received gemcitabine 125 mg/m2 weekly top of the same control group treatment. The primary end point was pathological response and toxicities along with patient compliance to treatment, late reactions, DFS and OS. Fifty patients were randomized between two arms. Results: The complete response in study and control arm was 96% and 88% respectively. Toxicities was significantly high in the study group compared to control group [leucopenia (P=0.015), skin reaction (P=0.03) and bleeding (P=0.019)]. Local recurrence rate: 8% in study arm, none in control arm. The distant failure prevailed in control arm (20% vs. 8%). On a median follow up of 21 months in control arm, the DFS was 73% whereas 83% in study arm in 16 months (P=0.69). OS in the study arm was 100% and 84.5% in the control arm (P=0.14). Conclusions: If the toxicity can be managed adequately in the combination chemo radiation group, it may produce an improvement in response. Survival benefit can also be obtained by introducing gemcitabine to cisplatin as radio sensitizer. [ABSTRACT FROM AUTHOR]

Multinuclear solid-state nuclear magnetic resonance (SSNMR) experiments have been performed on cisplatin and four related square-planar compounds. The wideband uniform rate smooth truncation - Carr-Purcell-Meiboom-Gill (WURST-CPMG) pulse sequence was utilized in NMR experiments to acquire 195Pt, 14N, and 35Cl ultra-wideline NMR spectra of high quality. Standard Hahn-echo and magic-angle spinning 195Pt NMR experiments are also performed to refine extracted chemical shielding (CS) tensor parameters. Platinum magnetic shielding (MS) tensor orientations are calculated using both plane-wave density functional theory (DFT) and standard DFT methods. The tensor orientations are shown to be highly constrained by molecular symmetry elements, but also influenced to some degree by intermolecular interactions. 14N WURST-CPMG experiments were performed on three compounds and electric field gradient (EFG) parameters (the quadrupolar coupling constant, CQ, and the asymmetry parameter, ηQ) are reported. First principles calculations of the 14N EFG tensor parameters and orientations and affirm their dependence on the local hydrogen bonding environment. 35Cl WURST-CPMG experiments on cisplatin and transplatin are reported, using two different static magnetic fields to extract EFG and CS tensor parameters, and 35Cl EFG tensor magnitudes and orientations are predicted using first principles calculations. Transverse ( T2) relaxation data for all nuclei are used to investigate heteronuclear dipolar relaxation mechanisms, as well as the nature of the local hydrogen bonding environments. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: To compare chemoradiation with systemic chemotherapy to chemotherapy alone in locally advanced pancreatic cancer. Patients and methods: One hundred and nineteen patients with locally advanced pancreatic cancer, with World Health Organization performance status of zero to two were randomly assigned to either the induction chemoradiation group (60 Gy, 2 Gy/fraction; concomitant 5-fluoro-uracil infusion, 300mg/m2 per day, days 1–5 for 6 weeks; cisplatin, 20mg/m2 per day, days 1–5 during weeks 1 and 5) or the induction gemcitabine group (GEM: 1000mg/m2 weekly for 7 weeks). Maintenance gemcitabine (1000mg/m2 weekly, 3/4 weeks) was given in both arms until disease progression or toxicity. Results: Overall survival was shorter in the chemoradiation than in the gemcitabine arm (median survival 8.6 [99% confidence interval 7.1–11.4] and 13 months [8,9,9–18], p =0.03). One-year survival was, respectively, 32 and 53%. These results were confirmed in a per-protocol analysis for patients who received 75% or more of the planned dose of radiotherapy. More overall grades 3–4 toxic effects were recorded in the chemoradiation arm, both during induction (36 versus 22%) and maintenance (32 versus 18%). Conclusion: This intensive induction schedule of chemoradiation was more toxic and less effective than gemcitabine alone. [Copyright &y& Elsevier]

Abstract: Purpose: To describe retrospectively the overall survival, the cancer specific survival and the tumor control in an homogeneous series of patients with epidermoid carcinoma of the anal canal treated with definitive radiotherapy; to assess the impact of brachytherapy, chemotherapy and pre-radiotherapy resection on the risk of recurrence. Patients and methods: From 1997 to 2007, 57 patients (pts) presenting with an epidermoid carcinoma of the anal canal (T1: 14, T2: 33, T3-4: 10, N0: 31, N1: 19, N2: 3, N3: 4, M0: 57) were treated with definitive radiotherapy by the same radiation oncologist. The treatment included an external beam irradiation (EBRT) given to the posterior pelvis (45Gy/25 fractions) and, six weeks later, a boost delivered with interstitial brachytherapy (37/57) or external beam irradiation (20/57). Twelve pts had undergone a surgical resection of the tumour before radiotherapy. A belly board was used for EBRT in 13 pts. A concurrent platinum based chemotherapy was done in 42 pts. The mean follow-up was 57 months. Results: The overall survival rate at 5 years was 89% with a cause specific survival of 96%. Five patients recurred (5-year rate: 12%: four had local relapse (5-year rate: 8%), four had groin recurrence, and distant metastases were seen in two. In univariate analysis, the risk of relapse was higher in patients who had undergone a pre-radiation excision (p =0.018), in those who did not receive chemotherapy (p =0.076) and in those who were irradiated on a belly board (p =0.049). In multivariate analysis, a pre-radiotherapy resection (p =0.084) had an inverse impact on the tumour control reaching the level of statistical significance and the use of a belly board was of marginal influence (p =0.13). Conclusion: Radiotherapy and chemoradiation with cisplatine-based chemotherapy cure a vast majority of patients with epidermoid carcinoma of the anal canal. Therapeutic factors that may interfere with the definition of the target volume and the patients’ repositioning may decrease the efficacy of radiotherapy. Pre-radiotherapy surgical resection should be avoided. [Copyright &y& Elsevier]

Abstract: Since 10 years, the combination of chemoradiotherapy has become a standard of treatment of the advanced localized cervical cancer. Two systematic reviews of the literature (including the results of the different clinical trials) have already been published. The aim of this article is to present the results of the recent meta-analysis based on individual patient data and to discuss the perspectives. This meta-analysis was rigorously designed: trials selected had the same control arm with the same radiotherapy without concomitant chemotherapy, the definition of the primary outcome (overall survival) was homogeneous and analysis was made in intent to treat. The results confirm the advantage in overall survival in favor of the chemoradiotherapy with an absolute 5-year overall survival benefit of 6% (60–66%) and 8% of 5-year disease-free survival (50–58%). Interestingly, even if cisplatin seems to be the most active drug, a significant advantage is also observed with no platinum chemotherapy. A polychemotherapy is not more active than a monochemotherapy and there was a suggestion of a difference in the size of the survival benefit with tumor stage. Larger benefits were seen for the few trials in which additional chemotherapy was administered after chemoradiotherapy, but results have to be confirmed by other clinical trials. Late toxicity was not well evaluated and a long-term follow-up of the patients is important to assess the real incidence of long-term side effects of the chemoradiotherapy and the impact on quality of life. New strategies combining new chemotherapy protocols or targeted therapy with radiation are promising but have to be evaluated in comparative clinical trials before use in routine. [Copyright &y& Elsevier]

Normal tissue toxicity resulting from chemoradiotherapy is of significant clinical concern. This study used normal Chinese hamster fibroblasts from lung (V79) and ovary (CHO-K1) to assess the modulation of cellular response to photons and neutrons by cisplatin, vinblastine, and bleomycin. Based on the colony formation assay, the drug concentration corresponding to 50% cell survival (EC50) of V79 cells was 1.50 ± 0.21 µmol/L for cisplatin, 0.97 ± 0.06 nmol/L for vinblastine, and 1.68 ± 0.11 µmol/L for bleomycin. The corresponding values for CHO-K1 cells were significantly lower for vinblastine (0.54 ± 0.02 nmol/L) and bleomycin (0.49 ± 0.13 µmol/L), but not for cisplatin (1.57 ± 0.20 µmol/L). No radiosensitivity enhancement was apparent when cells were exposed to p(66)/Be neutrons or photons (60Co γ-rays) in the presence of these drugs at EC50 concentrations. These data suggest that concurrent use of these drugs with radiation for the treatment of lung and ovarian diseases radiation does not exacerbate radiation-induced normal tissue toxicity, regardless of the quality of radiation. The relatively higher sensitivity of the ovarian cells to vinblastine and bleomycin might constitute a limitation in the use of these drugs for the treatment of lung lesions. [ABSTRACT FROM AUTHOR]

A series of chiral cis-dichloro(pyridyloxazoline)platinum(II) and palladium(II) complexes were synthesized and their reactivity towards a defined sequence of single-stranded and double-stranded DNA was investigated in comparison to cisplatin. The compounds differed in the nature and absolute configuration of the substituent at the C4 position of the oxazoline ring. The DNA-binding ability of these compounds was evaluated by HPLC analysis, post metal exposure, of enzymatic digests of an undecamer duplex containing one putative metallation site. Polyacrylamide gel electrophoresis (PAGE) and thermal denaturation confirmed the results of the HPLC analysis, which showed that the stereochemistry and character of the substituent at the C4 position of the oxazoline ring had little effect on DNA binding, possibly due to the formation of monofunctional adducts. [ABSTRACT FROM AUTHOR]

The effects of cisplatin exposure time, concentration, and irradiation sequence on the sensitivity of Chinese hamster lung fibroblasts (V79) to γ-ray exposure were examined. Based on clonogenic cell survival, the cisplatin concentrations corresponding to 50% cell survival (EC50) for exposure times of 1 h to 7 days followed a 2-phase exponential decay and ranged from 28.26 ± 3.32 to 1.53 ± 0.24 μmol/L, respectively. When cells were treated at EC50 for exposures of less than 4 h and irradiated immediately, cisplatin inhibited the effect of radiation. Exposures of 4-6 h did not affect radiosensitivity. For exposures of 8-12 h, radiosensitization was observed, which disappeared at 14 h and reappeared for much longer cisplatin treatments. At the lowest achievable EC50 (1.53 μmol/L), radiosensitization was observed if irradiation was delayed for 1-8 h. This enhancement in radiosensitivity disappeared for irradiation delays of 10-12 h, but reappeared when irradiation was delayed for 14-18 h. These data demonstrate that the mode of interaction between cisplatin and γ-irradiation depends on the concentration and exposure time of cisplatin, as well as on the timing of irradiation after cisplatin administration. Consideration of changes in cell cycle kinetics may contribute to the improvement of treatment outcomes in adjuvant chemoradiotherapy involving cisplatin. [ABSTRACT FROM AUTHOR]

Platinum agents have been used for almost 30 years in the treatment of many types of cancers. Cisplatin, carboplatin and oxaliplatin are the main compounds employed in France and the rest of Europe. They belong to the family of alkylating agents, exerting their cytotoxicity by forming DNA adducts. However, differences in chemical structure give them varied pharmacokinetic and pharmacodynamic properties. In this review, we summarize the cellular mechanisms involved in their cytotoxicity and resistance, pharmacokinetic and toxic characteristics and clinical use. [ABSTRACT FROM AUTHOR]

Polypyrimidine oligonucleotides can bind to tracts of contiguous purines in double-stranded DNA to form triple-stranded complexes. The stability of the triplex is reduced significantly if the target purine tract is interrupted by a single pyrimidine. Previous studies have shown that incorporation of an N4-aminoalkylcytosine into the triplex-forming oligonucleotide (TFO), opposite a single CG interruption, facilitates triplex formation. Examination of molecular models suggested that further modification of the amino group of the aminoalkyl arm might enable adduct formation with the N7 of the guanine of the CG interruption. To test this, we prepared 2′-deoxyribo-and 2′-O-methylribo-TFOs that contained cytosine (C), N4-(2-aminoethyl)cytosine (ae-C), or diethylenetriamineplatinum(II) (DPt-C) or cis-aquodiammineplatinum(II) (cPt-C) derivatives of N4-(2-aminoethyl)cytosine, positioned opposite a CG interruption of a polypurine tract found in the pol gene of HIV-1 proviral DNA. Although the C- and ae-C-derivatized deoxyribo-TFOs formed triplexes of modest stability and the DPt-C-modified TFO failed to form a triplex, the C- and ae-C-derivatized 2′-O-methylribo-TFOs formed remarkably stable triplexes (Tm = 57 °C). The DPt-C- and cPt-C-modified 2′-O-methylribo-TFOs also formed triplexes, although their stabilities were reduced (Tm = 33 °C), suggesting that the tethered platinum group may interfere sterically with TFO binding. Consistent with this hypothesis was the observation that triplex stability was restored (Tm = 57 °C) when the diethylenetriamineplatinum(II) group was tethered to the 5′-end of the 2′-O-methylribo-TFO via a 2-aminoethylcarbamate linkage. Taken together, these results suggest that 2′-O-methylribo-TFOs may be particularly useful in targeting purine tracts in DNA that have CG interruptions, and that further modification with platinum derivatives could lead to the design of TFOs that are capable of covalent binding to their target, thus increasing the effectiveness of the TFO.Key words: triplex-forming oligonucleotide, TFO, cisplatin, interrupted polypurine tract. [ABSTRACT FROM AUTHOR]

cis-Diamminedichloroplatinum (CDDP), commonly know as cisplatin, is a well known DNA-damaging agent, which is highly active in suppressing the proliferation of tumor cells. However, it is not clear that CDDP can induce growth inhibition of esophagus cancer cells. Using the cell line EC-109 from the esophagus, we found that CDDP would induce apoptotic responses. The addition of CDDP to cells led to the inhibition of growth in a time- and dose-dependent manner. CDDP generated reactive oxygen species (ROSs) in cells, which brought about a reduction in the intracellular mitochondrial transmembrane potential (Δψm), leading to apoptosis. Our findings demonstrate that ROSs, and the resulting oxidative stress, play a pivotal role in apoptosis. Preincubation of EC-109 cells with the hydrogen-peroxide-scavenging enzyme catalase partially inhibited the following: (i) the production of ROS; (ii) the disruption of the Δψm; and (iii) apoptosis. These results indicate that the enhancement of the generation of ROS and the disruption of Δψm are events involved in the apoptotic pathway of EC-109 induced by CDDP. [ABSTRACT FROM AUTHOR]

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Summary: Purpose: To evaluate the efficacy and safety of gemcitabine and carboplatin in the treatment of previously untreated patients with advanced non-small cell lung cancer (NSCLC). Methods: A randomized phase II study was conducted by the Groupe Français de Pneumo-Cancérologie (GFPC) in 15 centers. The patients were randomized in either arm A (GC): gemcitabine 1250mg/m2 on days 1 and 8+carboplatin AUC 6mg/(mLmin) on day 1; or in arm B (VP): vinorelbine 30mg/m2 weekly+cisplatin 80mg/m2 on day 1. Treatment cycles were repeated every 3 weeks. Results: A total of 100 patients were randomized with stage IV or stage III NSCLC with malignant pleural effusion: 51 patients in arm A and 49 patients in arm B. A total of 190 cycles were administered in the GC arm and 172 cycles in the VP arm, with a median of four cycles per patient in each arm. The dose intensity was 84.9% for gemcitabine, 99.8% for carboplatin, 97.7% for cisplatin and 67.7% for vinorelbine. The objective response rates were 19.6% (95% CI, 9.8–33.1) for GC and 29.2% (95% CI, 17.0–44.1) for VP in an ITT analysis. The response duration was 169 days in arm A and 226 days in arm B. The TTP was similar with 140 days (GC) and 148 days (VP), respectively. Overall survival rates were 334 days in the GC combination and 304 days in the VP combination. Overall, the treatment was safe and toxicities observed were different in each arm: neutropenia was the most common toxicity in the VP treatment, whereas thrombocytopenia was more frequent in the GC combination. Anemia was similar in both arms. Non-haematologic toxicity was mild. One toxic death in arm A and three toxic deaths in arm B were observed. Conclusion: In terms of response rate, the gemcitabine–carboplatin combination was not efficient enough to allow further phase III study. Survival data are in the same range as the standard arm. This chemotherapy is feasible and may represent an alternative to a standard cisplatin-based regimen, allowing treatment in an outpatient setting. [Copyright &y& Elsevier]

The therapeutic strategy of metastatic non-small cell lung cancer has greatly changed due to the availability of new chemotherapeutic regimens. Cisplatin based doublet regimen remains the standard treatment but new drug combinations are now available. Overall survival and response rates are nearly identical for all regimens but toxicity profiles are different. Treatment is chosen by the patient and his physician and multiple clinical and biological parameters are taken into account with the aim of maximizing the benefit to risk ratio and quality of life. In this review we discuss all different therapeutic options and their indications. [ABSTRACT FROM AUTHOR]

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The utilization of high linear energy transfer (LET) radiations, such as fast neutrons or carbon ions (hadrontherapy), offers promising perspectives in radiotherapy. While it is well known that by combining radiotherapy and chemotherapy, important therapeutic advantages can be obtained to cure cancer, there have been, so far, very few investigations on the effects of treatments combining an irradiation with high-LET particles and cancer drugs. The present study was therefore undertaken to examine the effects of exposure to 65 MeV fast neutrons combined with cisplatin in a murine T cell lymphoma (RDM4) in vitro. The cells were irradiated at doses ranging from 2 to 8 Gy without or with addition of cisplatin shortly before the irradiation, at concentrations between 0.3 and 12.5 µM. These treatments were applied concomitantly. Proliferation and apoptosis were assessed at different time intervals thereafter. The combination of irradiation with cisplatin was found to be more cytotoxic than either treatment alone. Furthermore, the cytotoxicity induced by this cotreatment resulted not only from apoptosis but also from other forms of cell death. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world. A wide variety of treatment modalities is available for palliative therapy of HCC, although there is no strong evidence that these treatments can have a significant impact on survival. The aim of this work was to screen cytotoxic drugs relevant in the treatment of HCC for enhancement of the effect of irradiation in an in vitro model. As the majority of patients presenting with HCC suffer reduced liver function, attention was paid to low-dose effects of the cytotoxic drugs tested. To reflect this situation in vivo, multicellular tumor aggregates or "spheroids" of HepG2 cells were cultured and exposed to gamma irradiation alone or in combination with cisplatin for 4 h, gemcitabin for 4 or 24 h, or 5-fluorouracil for 4 h. In one experiment, the spheroids were cultured for 4 weeks in multiwell plates that allowed adhesion. Measurement of two-dimensional spheroid outgrowth was made every week for each spheroid. This kind of growth depends on the proliferation and motility of the cells that form the spheroid. In a second experiment, toxicity was evaluated by comparative growth curves by means of a three-dimensional growth assay and by histology. Supra-additive effects lasting for 4 weeks were observed for all drugs tested in combination with a gamma irradiation of 10 Gy. [ABSTRACT FROM AUTHOR]