Olaparib treatment significantly improved objective response rate (primary end point) and progression-free survival versus nonplatinum chemotherapy in patients with BRCA-mutated platinum-sensitive relapsed ovarian cancer in the open-label phase III SOLO3 trial (ClinicalTrials.gov identifier: NCT02282020). We report final overall survival (OS; prespecified secondary end point), post hoc OS analysis by number of previous chemotherapy lines, and exploratory BRCA reversion mutation analysis. Two hundred sixty-six patients were randomly assigned 2:1 to olaparib tablets (300 mg twice daily; n = 178) or physician's choice of single-agent nonplatinum chemotherapy (pegylated liposomal doxorubicin, paclitaxel, gemcitabine, or topotecan; n = 88). OS was similar with olaparib versus chemotherapy (hazard ratio [HR], 1.07 [95% CI, 0.76 to 1.49]; P = .71, median 34.9 and 32.9 months, respectively, full analysis set). OS with olaparib was favorable in patients with two previous chemotherapy lines (HR, 0.83 [olaparib v chemotherapy] [95% CI, 0.51 to 1.38]; median 37.9 v 28.8 months); however, a potential detrimental effect was seen in patients with at least three previous chemotherapy lines (HR, 1.33 [95% CI, 0.84 to 2.18]; median 29.9 v 39.4 months). BRCA reversion mutations might have contributed to this finding. No patient randomly assigned to olaparib with a BRCA reversion mutation detected at baseline (6 of 170 [3.5%]) achieved an objective tumor response.

• MeSH
• deoxycytidin analogy a deriváty   aplikace a dávkování   MeSH
• doba přežití bez progrese choroby MeSH
• dospělí MeSH
• doxorubicin analogy a deriváty   aplikace a dávkování   MeSH
• ftalaziny * terapeutické užití   škodlivé účinky   aplikace a dávkování   MeSH
• gemcitabin MeSH
• lidé středního věku MeSH
• lidé MeSH
• lokální recidiva nádoru * farmakoterapie   MeSH
• nádory vaječníků * farmakoterapie   genetika   mortalita   patologie   MeSH
• paclitaxel aplikace a dávkování   MeSH
• PARP inhibitory * terapeutické užití   škodlivé účinky   MeSH
• piperaziny * terapeutické užití   škodlivé účinky   aplikace a dávkování   MeSH
• polyethylenglykoly aplikace a dávkování   MeSH
• protein BRCA1 genetika   MeSH
• protein BRCA2 genetika   MeSH
• protokoly protinádorové kombinované chemoterapie * terapeutické užití   škodlivé účinky   MeSH
• senioři MeSH
• topotekan aplikace a dávkování   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• BRCA1 protein, human MeSH Prohlížeč
• BRCA2 protein, human MeSH Prohlížeč
• deoxycytidin MeSH
• doxorubicin MeSH
• ftalaziny * MeSH
• gemcitabin MeSH
• liposomal doxorubicin MeSH Prohlížeč
• olaparib MeSH Prohlížeč
• paclitaxel MeSH
• PARP inhibitory * MeSH
• piperaziny * MeSH
• polyethylenglykoly MeSH
• protein BRCA1 MeSH
• protein BRCA2 MeSH
• topotekan MeSH

Topotecan (TPT) is used in the treatment of retinoblastoma, the most common malignant intraocular tumor in children. TPT undergoes pH-dependent hydrolysis of the lactone ring to the ring-opened carboxylate form, with the lactone form showing antitumor activity. A selective, and highly sensitive ultra-high-performance liquid chromatography-tandem mass spectrometry method was developed for the determination of both forms of TPT in one mobile phase composition in plasma and vitreous humor matrices. The method showed an excellent linear range of 0.375-120 ng/mL for the lactone. For the carboxylate, the linear range was from 0.75 to 120 ng/mL. The matrix effect and the recovery for the lactone ranged from 98.5% to 106.0% in both matrices, for the carboxylate form, it ranged from 94.9% to 101.2%. The dynamics of the transition between TPT lactone and TPT carboxylate were evaluated at different pH environments. The stability of TPT forms was assessed in plasma and vitreous humor at 8 and 37°C and a very fast conversion of lactone to carboxylate form occurred at 37°C in both matrices. The method developed facilitates the investigation of TPT pharmacodynamics and the release kinetics in the development of the innovative local drug delivery systems.

• Klíčová slova
• UHPLC‐MS/MS, anti‐cancer drug topotecan, carboxylate form, lactone form, topotecan stability,
• MeSH
• kyseliny karboxylové chemie   analýza   MeSH
• laktony * chemie   analýza   MeSH
• lidé MeSH
• molekulární struktura MeSH
• sklivec * chemie   MeSH
• tandemová hmotnostní spektrometrie * MeSH
• topotekan * chemie   analýza   MeSH
• vysokoúčinná kapalinová chromatografie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• kyseliny karboxylové MeSH
• laktony * MeSH
• topotekan * MeSH

BACKGROUND: Lurbinectedin is a synthetic marine-derived anticancer agent that acts as a selective inhibitor of oncogenic transcription. Lurbinectedin monotherapy (3·2 mg/m2 every 3 weeks) received accelerated approval from the US Food and Drug Administration on the basis of efficacy in patients with small-cell lung cancer (SCLC) who relapsed after first-line platinum-based chemotherapy. The ATLANTIS trial assessed the efficacy and safety of combination lurbinectedin and the anthracycline doxorubicin as second-line treatment for SCLC. METHODS: In this phase 3, open-label, randomised study, adult patients aged 18 years or older with SCLC who relapsed after platinum-based chemotherapy were recruited from 135 hospitals across North America, South America, Europe, and the Middle East. Patients were randomly assigned (1:1) centrally by dynamic allocation to intravenous lurbinectedin 2·0 mg/m2 plus doxorubicin 40·0 mg/m2 administered on day 1 of 21-day cycles or physician's choice of control therapy (intravenous topotecan 1·5 mg/m2 on days 1-5 of 21-day cycles; or intravenous cyclophosphamide 1000 mg/m2, doxorubicin 45·0 mg/m2, and vincristine 2·0 mg on day 1 of 21-day cycles [CAV]) administered until disease progression or unacceptable toxicity. Primary granulocyte-colony stimulating factor prophylaxis was mandatory in both treatment groups. Neither patients nor clinicians were masked to treatment allocation, but the independent review committee, which assessed outcomes, was masked to patients' treatment allocation. The primary endpoint was overall survival in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02566993, and with EudraCT, 2015-001641-89, and is complete. FINDINGS: Between Aug 30, 2016, and Aug 20, 2018, 613 patients were randomly assigned to lurbinectedin plus doxorubicin (n=307) or control (topotecan, n=127; CAV, n=179) and comprised the intention-to-treat population; safety endpoints were assessed in patients who had received any partial or complete study treatment infusions (lurbinectedin plus doxorubicin, n=303; control, n=289). After a median follow-up of 24·1 months (95% CI 21·7-26·3), 303 patients in the lurbinectedin plus doxorubicin group and 289 patients in the control group had discontinued study treatment; progressive disease was the most common reason for discontinuation (213 [70%] patients in the lurbinectedin plus doxorubicin group vs 152 [53%] in the control group). Median overall survival was 8·6 months (95% CI 7·1-9·4) in the lurbinectedin plus doxorubicin group versus 7·6 months (6·6-8·2) in the control group (stratified log-rank p=0·90; hazard ratio 0·97 [95% CI 0·82-1·15], p=0·70). 12 patients died because of treatment-related adverse events: two (<1%) of 303 in the lurbinectedin plus doxorubicin group and ten (3%) of 289 in the control group. 296 (98%) of 303 patients in the lurbinectedin plus doxorubicin group had treatment-emergent adverse events compared with 284 (98%) of 289 patients in the control group; treatment-related adverse events occurred in 268 (88%) patients in the lurbinectedin plus doxorubicin group and 266 (92%) patients in the control group. Grade 3 or worse haematological adverse events were less frequent in the lurbinectedin plus doxorubicin group than the control group (anaemia, 57 [19%] of 302 patients in the lurbinectedin plus doxorubicin group vs 110 [38%] of 288 in the control group; neutropenia, 112 [37%] vs 200 [69%]; thrombocytopenia, 42 [14%] vs 90 [31%]). The frequency of treatment-related adverse events leading to treatment discontinuation was lower in the lurbinectedin plus doxorubicin group than in the control group (26 [9%] of 303 patients in the lurbinectedin plus doxorubicin group vs 47 [16%] of 289 in the control group). INTERPRETATION: Combination therapy with lurbinectedin plus doxorubicin did not improve overall survival versus control in patients with relapsed SCLC. However, lurbinectedin plus doxorubicin showed a favourable haematological safety profile compared with control. FUNDING: PharmaMar.

• MeSH
• dospělí MeSH
• doxorubicin škodlivé účinky   MeSH
• lékaři * MeSH
• lidé MeSH
• nádory plic * etiologie   MeSH
• protokoly protinádorové kombinované chemoterapie škodlivé účinky   MeSH
• topotekan terapeutické užití   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• doxorubicin MeSH
• PM 01183 MeSH Prohlížeč
• topotekan MeSH

Treatment of retinoblastoma (Rb) has greatly improved in recent years in terms of survival and eye salvage rates, using mainly intra-arterial or intravitreal chemotherapy. However, the treatment of vitreous tumor seeding still represents a challenge and it is of great interest to develop new strategies to deliver pharmacologically sufficient drug amounts to the vitreous humor. In the present work, we present a lens-shaped bi-layered hydrogel implant for delivery of topotecan (TPT) via transscleral diffusion. The implant consists of an inner TPT-loaded poly(2-hydroxyethyl methacrylate) (pHEMA) layer adjacent to the sclera and an outer covering poly(2-ethoxyethyl methacrylate) (pEOEMA) layer impermeable to TPT. TPT-loaded pHEMA samples exhibit long-lasting in vitro cytotoxicity against the Rb cell line Y79. In an in vivo experiment, pHEMA/pEOEMA implants are successfully surgically administered to the posterior segment of rabbit eyes. The determination of TPT pharmacokinetics demonstrates the attainment of promising levels of TPT (10 ng/ml) in vitreous humor 8 h after implant placement. The results from the pilot experiment constitute the proof of principle for the use of the proposed implants as a drug delivery system for the local treatment of intraocular diseases.

• Klíčová slova
• HEMA, Hydrogel, Intraocular delivery, Retinoblastoma, Topotecan, Transscleral diffusion,
• MeSH
• hydrogely MeSH
• králíci MeSH
• nádory sítnice * MeSH
• retinoblastom * MeSH
• sklivec MeSH
• topotekan MeSH
• zvířata MeSH
• Check Tag
• králíci MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• hydrogely MeSH
• topotekan MeSH

PURPOSE: Low-grade serous ovarian carcinomas (LGSOCs) have historically low chemotherapy responses. Alterations affecting the MAPK pathway, most commonly KRAS/BRAF, are present in 30%-60% of LGSOCs. The purpose of this study was to evaluate binimetinib, a potent MEK1/2 inhibitor with demonstrated activity across multiple cancers, in LGSOC. METHODS: This was a 2:1 randomized study of binimetinib (45 mg twice daily) versus physician's choice chemotherapy (PCC). Eligible patients had recurrent measurable LGSOC after ≥ 1 prior platinum-based chemotherapy but ≤ 3 prior chemotherapy lines. The primary end point was progression-free survival (PFS) by blinded independent central review (BICR); additional assessments included overall survival (OS), overall response rate (ORR), duration of response (DOR), clinical-benefit rate, biomarkers, and safety. RESULTS: A total of 303 patients were randomly assigned to an arm of the study at the time of interim analysis (January 20, 2016). Median PFS by BICR was 9.1 months (95% CI, 7.3 to 11.3) for binimetinib and 10.6 months (95% CI, 9.2 to 14.5) for PCC (hazard ratio,1.21; 95%CI, 0.79 to 1.86), resulting in early study closure according to a prespecified futility boundary after 341 patients had enrolled. Secondary efficacy end points were similar in the two groups: ORR 16% (complete response [CR]/partial responses[PRs], 32) versus 13% (CR/PRs, 13); median DOR, 8.1 months (range, 0.03 to ≥ 12.0 months) versus 6.7 months (0.03 to ≥ 9.7 months); and median OS, 25.3 versus 20.8 months for binimetinib and PCC, respectively. Safety results were consistent with the known safety profile of binimetinib; the most common grade ≥ 3 event was increased blood creatine kinase level (26%). Post hoc analysis suggests a possible association between KRAS mutation and response to binimetinib. Results from an updated analysis (n = 341; January 2019) were consistent. CONCLUSION: Although the MEK Inhibitor in Low-Grade Serous Ovarian Cancer Study did not meet its primary end point, binimetinib showed activity in LGSOC across the efficacy end points evaluated. A higher response to chemotherapy than expected was observed and KRAS mutation might predict response to binimetinib.

• MeSH
• benzimidazoly škodlivé účinky   terapeutické užití   MeSH
• doba přežití bez progrese choroby MeSH
• dospělí MeSH
• doxorubicin analogy a deriváty   terapeutické užití   MeSH
• inhibitory proteinkinas škodlivé účinky   terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• lokální recidiva nádoru farmakoterapie   MeSH
• MAP kinasa-kinasa 1 antagonisté a inhibitory   MeSH
• MAP kinasa-kinasa 2 antagonisté a inhibitory   MeSH
• mladý dospělý MeSH
• nádory vaječníků farmakoterapie   enzymologie   patologie   MeSH
• nádory vejcovodů farmakoterapie   enzymologie   patologie   MeSH
• paclitaxel terapeutické užití   MeSH
• peritoneální nádory farmakoterapie   enzymologie   patologie   MeSH
• polyethylenglykoly terapeutické užití   MeSH
• senioři MeSH
• serózní cystadenokarcinom farmakoterapie   enzymologie   patologie   MeSH
• stupeň nádoru MeSH
• topotekan terapeutické užití   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• benzimidazoly MeSH
• binimetinib MeSH Prohlížeč
• doxorubicin MeSH
• inhibitory proteinkinas MeSH
• liposomal doxorubicin MeSH Prohlížeč
• MAP kinasa-kinasa 1 MeSH
• MAP kinasa-kinasa 2 MeSH
• MAP2K1 protein, human MeSH Prohlížeč
• MAP2K2 protein, human MeSH Prohlížeč
• paclitaxel MeSH
• polyethylenglykoly MeSH
• topotekan MeSH

Retinoblastoma (Rb) is the most common primary malignant intraocular tumor in children which develops from the retinal stem cells. Systemic chemotherapy is the typical therapeutic treatment and though most children survive Rb, they often lose their vision, or the eye needs to be enucleated. Regarding to the pure availability of the target tumor by systemic chemotherapy, the local anticancer drug administration would be advantageous to increase the local drug concentration and minimize adverse side effects of chemotherapy. The present paper describes a new hydrogel implant enabled to deliver therapeutically active doses of low molecular weight hydrophilic antitumor drugs topotecan and vincristine. The hydrogel implant is proposed as bi-layered with an inner hydrophilic layer from 2-hydroxyethyl methacrylate (HEMA) serving as a reservoir of the chemotherapeutic agent and an outer hydrophobic layer from 2-ethoxyethyl methacrylate (EOEMA) acting as a barrier to protect the surrounding vascularized tissue against cytotoxicity of the delivered chemotherapeutics. The experiments with enucleated pig eyes demonstrated the ability of tested drugs to diffuse through sclera and reach the vitreous humor. HEMA-based hydrogels were examined in terms of sorption, release and transport properties, showing the possibility of adjusting the loading capacity and diffusion of the drugs by the degree of crosslinking. The EOEMA-based gels proved to be an inert for drug sorption and diffusion. A chorioallantoic membrane assay demonstrated excellent biocompatibility of unloaded hydrogels, and in vitro experiments confirmed significant cytotoxicity of drug-loaded hydrogels against a Rb cell line; 2 days for those topotecan-loaded and a minimum of 6 days for vincristine-loaded hydrogels. The bi-layered hydrogel implant can be considered promising for local administration of active agents to eye-globe for the treatment of Rb and also other ocular disorders.

• Klíčová slova
• Local chemotherapy, Methacrylate hydrogels, Retinoblastoma, Topotecan, Transscleral delivery, Vincristine,
• MeSH
• hydrogely chemie   MeSH
• kinetika MeSH
• lidé MeSH
• methakryláty chemie   MeSH
• nádorové buněčné linie MeSH
• nosiče léků chemie   MeSH
• oči účinky léků   metabolismus   MeSH
• prasata MeSH
• protézy a implantáty MeSH
• retinoblastom metabolismus   patologie   MeSH
• stabilita léku MeSH
• topotekan chemie   metabolismus   farmakologie   MeSH
• viabilita buněk účinky léků   MeSH
• vinkristin chemie   metabolismus   farmakologie   MeSH
• vysokoúčinná kapalinová chromatografie MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• hydrogely MeSH
• hydroxyethyl methacrylate MeSH Prohlížeč
• methakryláty MeSH
• nosiče léků MeSH
• topotekan MeSH
• vinkristin MeSH

AIM: To determine intravitreal and plasma concentrations and retinal toxicity after transcorneal intravitreal injection of 1 μg and 2 μg of topotecan (Hycamtin). METHOD: Twelve healthy albino rabbits were included in this in vivo experiment. Six anesthetized albino rabbits received a single transcorneal intravitreal injection of 1 μg (group A) or 2 μg (group B) of topotecan. Vitreous and blood samples were collected until 168 h. Left eyes were treated with the same volume of saline. Plasma and vitreous levels of topotecan were determined by high-performance liquid chromatography. Area under the plasma concentration time curve (AUC) was calculated using trapezoidal rule. Clinical evidence of toxicity was classified into four grades according to anatomical structures. Electroretinograms (ERGs) were recorded. RESULTS: Time to maximum concentration was observed up to 2 h after drug injection in group A whereas up to 1 h in group B. Low levels of topotecan were detected in plasma in both groups and in the vitreous humor of the contralateral eye in group B. Topotecan levels (mean vitreous AUC in group A 2.55 μg/mL.h and in group B 5.338 μg/mL.h) were detectable up to 6 h in both groups. We observed following structural changes in rabbit eyes: corneal vascularization, cataract, hemophthalmus, choroidal edema and focal retinal atrophy. Abnormal ERGs were obtained. CONCLUSION: Our findings proved that transcorneal intravitreal administration of 1 μg and 2 μg of topotecan results in potentially cytotoxic intraocular concentrations. More studies are needed to establish the safety of topotecan for retinoblastoma in children.

• MeSH
• inhibitory topoisomerasy I aplikace a dávkování   analýza   krev   MeSH
• králíci MeSH
• nádory sítnice farmakoterapie   MeSH
• retina účinky léků   MeSH
• retinoblastom farmakoterapie   MeSH
• sklivec chemie   MeSH
• topotekan aplikace a dávkování   analýza   krev   MeSH
• zvířata MeSH
• Check Tag
• králíci MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• inhibitory topoisomerasy I MeSH
• topotekan MeSH

Ovarian carcinoma represents the most common cause of death from gynecological malignancies in Europe and North America, being the third most frequent and the first as to the mortality. The standard chemotherapeutical regimen for ovarian cancer involves the administration of platinum derivate (carboplatin, cisplatin), in advanced stage is platinum derivate combined with paclitaxel. Introducing chemoresistance testing of ovarian tumour cells may help to choose optimal chemotherapeutic drug and customize the individual chemotherapeutical regimens in patients. One of approaches of individualization of chemotherapy is in vitro chemosensitivity testing. In our study, we evaluated the cytotoxic effects of selected chemotherapeutics in cells isolated from ovarian tumours and ascites of individual patients. Panel of chemotherapeutics used in the study included cisplatin, paclitaxel, carboplatin, topotecan, gemcitabine and etoposide and their effects on cell viability were determined by the MTT assay. In the total number of 32 clinical samples of tumour and ascites cells, the highest sensitivity showed cells to topotecan, sensitivity to cisplatin was higher than to carboplatin and paclitaxel used in clinical practice showed most often only the marginal reactivity. Resistance to carboplatin and most of the time to gemcitabine and etoposide was commonly present. When the same test on cells that have been frozen for several weeks was repeated it was found that in 20 cases chemosensitivity increased while in 18 cases decreased. In remaining cases there was no change in reactivity to cytostatics. Moreover, chemosensitivity of cells isolated from solid tumour and ascites from the same patient did not show any significant difference with exaption of paclitaxel.

• MeSH
• biologické modely MeSH
• chemorezistence * MeSH
• cisplatina toxicita   MeSH
• deoxycytidin analogy a deriváty   toxicita   MeSH
• etoposid toxicita   MeSH
• gemcitabin MeSH
• karboplatina toxicita   MeSH
• karcinom farmakoterapie   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nádory vaječníků farmakoterapie   MeSH
• paclitaxel toxicita   MeSH
• protinádorové látky toxicita   MeSH
• screeningové testy protinádorových léčiv MeSH
• topotekan toxicita   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cisplatina MeSH
• deoxycytidin MeSH
• etoposid MeSH
• gemcitabin MeSH
• karboplatina MeSH
• paclitaxel MeSH
• protinádorové látky MeSH
• topotekan MeSH