RESUMO
PURPOSE: TMX-101 and TMX-202 are formulations of toll-like receptor 7 (TLR-7) agonists, under investigation for the treatment of urothelial carcinoma. Our goal was to evaluate the efficacy of intravesical instillations of TMX-101 or TMX-202 in an orthotopic bladder cancer rat model. METHODS: Four groups of 14 rats received an instillation with isogenic AY-27 tumor cells on day 0, starting tumor development. On day 2 and 5, the rats were treated with an intravesical instillation of TMX-101 0.1%, TMX-202 0.38%, vehicle solution or NaCl. On day 12 the rats were sacrificed and the bladders were evaluated histopathologically. RESULTS: No signs of toxicity were seen. The number of tumor-positive rats was 11 of 14 (79%) in the vehicle control group and in the NaCl control group, versus 9 of 14 (64%) in the TMX-101-treated group, and 8 of 14 (57%) in the TMX-20-treated group. The difference between tumor-bearing rats in the treated and control groups was not significant (p = 0.12). Bladder weight was significantly lower for TMX-202-treated rats compared to vehicle (p = 0.005). CONCLUSIONS: TMX-101 and TMX-202 are TLR-7 agonists with antitumor activity. Treatment with TMX-101 and TMX-202 resulted in less tumor-bearing rats compared to vehicle or saline control groups, although not statistically significant. In this aggressive bladder cancer model, a lower number of tumor-positive rats after treatment with TLR-7 agonists indicates activity for the treatment of non-muscle invasive bladder cancer.
Assuntos
Adenina/análogos & derivados , Carcinoma de Células de Transição/tratamento farmacológico , Glicerofosfolipídeos/farmacologia , Imiquimode/farmacologia , Fatores Imunológicos/farmacologia , Receptor 7 Toll-Like/agonistas , Neoplasias da Bexiga Urinária/tratamento farmacológico , Bexiga Urinária/efeitos dos fármacos , Adenina/farmacologia , Adjuvantes Imunológicos/farmacologia , Administração Intravesical , Animais , Carcinoma de Células de Transição/patologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Ratos , Ratos Endogâmicos F344 , Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/patologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
OBJECTIVES: To evaluate and compare the pharmacokinetic and pharmacodynamic properties of 2 investigational Toll-like receptor 7 agonists, TMX-101, and TMX-202 after intravenous and intravesical administration in a rat model. TLR-7 agonists are successfully used as topical treatment for various (pre)malignant skin lesions and are now under investigation as intravesical therapy for non-muscle-invasive bladder cancer. METHODS: Rats received an intravesical instillation with TMX-101, TMX-202, or vehicle. Additionally 2 groups of rats received an intravenous injection with TMX-101 or TMX-202. Blood sampling was performed at different time points, including pre-exposure and postexposure to determine the plasma concentrations of study drugs for pharmacokinetic and pharmacodynamic analyses and to determine the plasma concentrations of cytokines (IL-2, IL-6, and TNF-α). RESULTS: We observed no signs of toxicity after intravesical or intravenous administration. There was a limited dose dependent systemic uptake of TMX-101 and TMX-202 after intravesical administration. The systemic uptake of TMX-202 after intravesical instillation was 25 times lower compared to TMX-101. CONCLUSIONS: This in vivo study confirms the safety of intravesical TMX-101 and TMX-202 administration, with TMX-202 showing lower systemic uptake. TMX-202 has a larger molecule-mass compared to TMX-101, and it may therefore have a favorable safety profile when treating patients with non-muscle-invasive bladder cancer intravesically.
Assuntos
Adenina/análogos & derivados , Aminoquinolinas/farmacologia , Aminoquinolinas/farmacocinética , Modelos Animais de Doenças , Glicerofosfolipídeos/farmacologia , Glicerofosfolipídeos/farmacocinética , Receptor 7 Toll-Like/agonistas , Neoplasias da Bexiga Urinária/tratamento farmacológico , Adenina/administração & dosagem , Adenina/farmacocinética , Adenina/farmacologia , Administração Intravenosa , Administração Intravesical , Aminoquinolinas/administração & dosagem , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Feminino , Glicerofosfolipídeos/administração & dosagem , Ratos , Ratos Endogâmicos F344 , Distribuição Tecidual , Neoplasias da Bexiga Urinária/patologiaRESUMO
INTRODUCTION: Non-muscle invasive bladder cancer (NMIBC) is a highly recurrent disease with potential progression to muscle invasive disease despite the standard bladder instillations with mitomycin C (MMC) or Bacille Calmette-Guérin immunotherapy. Therefore, alternatives such as radiofrequency-induced chemohyperthermia (RF-CHT) with MMC are being investigated. The mechanism explaining the efficacy of RF-CHT is only partly understood. We examined whether RF-CHT results in higher MMC tissue concentrations as compared to cold MMC instillation. PATIENTS AND METHODS: Prior to a planned transurethral resection of bladder tumour (TURBT), patients with stage Ta NMIBC were allocated to either (1) cold MMC instillation or (2) RF-CHT. After MMC instillation, three biopsies were taken of both normal and tumour tissue. Biopsies were snap-frozen and MMC tissue concentrations were analysed using ultra-performance liquid chromatography. RESULTS: Eleven patients were included of which six received RF-CHT. Ten patients had TaG2-LG/HG papillary tumours at pathology. One patient in the RF-CHT group appeared to be free of malignancy and was excluded from the analysis as no tumour biopsies were available. The median MMC concentration in tumour tissue was higher in the RF-CHT group (median 665.00 ng/g vs. 63.75 ng/g, U = 51.0, p = 0.018). Moreover, in both techniques the MMC concentration was lower in normal tissue compared to tumour tissue. Tissue MMC concentration measurements varied substantially within, and between, different patients from the same group. CONCLUSION: Intravesical RF-CHT results in higher tumour MMC concentrations vs. cold MMC instillation which contributes to its superior efficacy.
Assuntos
Hipertermia Induzida/métodos , Mitomicina/uso terapêutico , Neoplasias da Bexiga Urinária/terapia , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mitomicina/farmacologia , Neoplasias da Bexiga Urinária/patologiaRESUMO
INTRODUCTION/BACKGROUND: Non-muscle-invasive bladder cancer (NMIBC) has a strong tendency to recur despite adjuvant instillations. TMX-101 is a new liquid form of imiquimod for intravesical instillation and has activity in vitro against urothelial carcinoma. The purpose was to analyze the activity of TMX-101 in low-grade NMIBC. Furthermore, pharmacokinetic and pharmacodynamic characteristics and adverse events were evaluated. PATIENTS AND METHODS: A multicenter, prospective phase 1 trial in 7 patients with low-grade NMIBC was conducted. All patients underwent a marker lesion transurethral resection of the bladder tumor and 6 weekly instillations with TMX-101 0.2% or 0.4%. Cystoscopy 2 to 4 weeks after the last instillation evaluated the effect of TMX-101. RESULTS: The effective biologic dose (EBD = complete response [CR] in > 2 patients) could not be defined because none of the patients experienced CR. Maximum plasma concentration was 75.1 ng/mL in the 0.4% dose group. No drug accumulation was observed. In the pharmacodynamic analysis, urinary interleukin 1 receptor agonist (IL-1ra) represents the most sensitive and uniform response after TMX-101 instillation. A total of 87.0% reported at least 1 adverse event. All events were of grade 2 severity or less (Common Terminology Criteria of Adverse Events version 4.02). No clinically significant changes in laboratory parameters or vital signs were observed during or after treatment. CONCLUSION: Toll-like receptor 7 (TLR-7) agonists are effective in urothelial carcinoma in preclinical research. The EBD in this phase 1 study could not be determined because no patient experienced CR. IL-1ra could be valuable as a urinary biomarker in future developments. The safety of TMX-101 has been reconfirmed. New doses, other schedules, and NMIBC subgroups should be tested to define the EBD. A pilot study in carcinoma-in-situ patients is currently ongoing and results are expected shortly.
Assuntos
Aminoquinolinas/administração & dosagem , Antineoplásicos/administração & dosagem , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Administração Intravesical , Aminoquinolinas/efeitos adversos , Aminoquinolinas/farmacocinética , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/cirurgia , Cistoscopia , Relação Dose-Resposta a Droga , Feminino , Humanos , Imiquimode , Proteína Antagonista do Receptor de Interleucina 1/urina , Neoplasias Renais/patologia , Neoplasias Renais/cirurgia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do TratamentoRESUMO
OBJECTIVES: To explore whether urinary cytokine and chemokine (CK) levels differed between cold mitomycin-C (cold-MMC)-treated patients and chemohyperthermia (C-HT)-treated patients, to shed light on the possible molecular mechanisms that might explain the superior outcome of C-HT. Furthermore, CK-differences were explored between C-HT responders and C-HT non-responders. METHODS: Twelve NMIBC patients were included. Nine received six-weekly C-HT, and three received four-weekly cold-MMC instillations. Urine was collected on 8-12 time points before and after every treatment. MDC, IL-2, IL-6, IL-8, IP-10, MCP-1 and RANTES were determined by Luminex(®)-analysis. RESULTS: Elevated urinary CK levels were observed in both groups after treatment. In general, CK-peaks were lower in the cold-MMC group in comparison with levels in the C-HT group. Significant higher MCP-1 and IL-6 levels were observed in C-HT-treated patients. Additionally, significant cumulative effects were observed for IP-10 and IL-2. However, IP-10 and IL-2 levels did not significantly differ between treatments. MDC levels after the first week of treatment were significantly higher in the C-HT responders compared with the non-responders. CONCLUSION: MMC treatment leads to elevated urinary CK levels with significantly higher MCP-1 and IL-6 levels in C-HT-treated patients. Increased MDC levels after the first C-HT instillation appear to be related to good clinical outcome and might be of additional value to personalize treatment. Studies involving more patients and longer follow-up are needed to substantiate this observation.
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Carcinoma de Células de Transição/terapia , Citocinas/urina , Hipertermia Induzida/métodos , Mitomicina/administração & dosagem , Neoplasias da Bexiga Urinária/terapia , Administração Intravesical , Idoso , Idoso de 80 Anos ou mais , Antibióticos Antineoplásicos/administração & dosagem , Biomarcadores Tumorais/urina , Carcinoma de Células de Transição/patologia , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Instilação de Medicamentos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento , Neoplasias da Bexiga Urinária/patologiaRESUMO
OBJECTIVES: In this in vitro study, we determined whether meso-tetraphenyl chlorin disulphonate (TPCS2a)-based photochemical delivery of bleomycin was able to potentiate the cytotoxicity of bleomycin on bladder cancer cells. MATERIALS AND METHODS: The human RT4, RT112, 253J, T24, and rat AY-27 urothelial carcinoma cell lines were used. Cells were seeded in 96-well plates. TPCS2a was added to the growth medium and the plates were incubated overnight. Cells were then resuspended in TPCS2a-free culture medium and incubated for 3 hours. Subsequently, cells were treated for 60 minutes with increasing doses of epirubicin, gemcitabine, mitomycin C, or bleomycin followed by illumination for different periods. Cell viability was measured with a colorimetric assay after 72 hours. RESULTS: For the single treatments, in all 5 cell lines a dose-dependent inhibition of cell proliferation was observed. This was seen both after treatment with TPCS2a-based photodynamic therapy (PDT), as well as after treatment with either bleomycin or one of the control chemotherapeutic agents. After treatment with PDT (240-s illumination), bleomycin 9.0 µM, and the combination of these treatments, relative survival percentages were 89.2 ± 13.0, 70.2 ± 8.9, and 30.5 ± 6.1, respectively, in the T24 cell line. After treatment with PDT (120-s illumination), bleomycin 27 µM and the combination of these treatments, relative survival percentages were 93.6 ± 15.7, 74.7 ± 9.6, and 30.0 ± 11.1, respectively, in the AY-27 cell line. In both cell lines, PDT combined with bleomycin showed significantly (P<0.001) higher cell kill than the sum of the single treatments, suggesting a photochemical internalization effect. CONCLUSIONS: TPCS2a-based photochemical internalization of bleomycin showed a significant, at least, additive antiproliferative activity against human and rat urothelial carcinoma cells in vitro. Thus, photochemical internalization may have therapeutic potential as an intravesical strategy against bladder cancer. As the effect is heterogeneous, biomarker studies are warranted to be able to predict the effects of a photochemical internalization-based treatment.
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Bleomicina/farmacologia , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Luz , Animais , Antibióticos Antineoplásicos/farmacologia , Carcinoma de Células de Transição/tratamento farmacológico , Carcinoma de Células de Transição/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Epirubicina/farmacologia , Humanos , Mitomicina/farmacologia , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/farmacologia , Porfirinas/farmacologia , Ratos , Fatores de Tempo , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/patologia , GencitabinaRESUMO
PURPOSE: Imiquimod, a toll like receptor 7 (TLR-7) agonist, is effective as a topical treatment for skin malignancies. TMX-101 is a liquid formulation of imiquimod. In this study we establish a safety profile of TMX-101 in patients with nonmuscle invasive bladder cancer. MATERIALS AND METHODS: We conducted a multicenter phase 1 dose escalation study in patients with nonmuscle invasive bladder cancer. Patients were included in 1 of 4 dose groups (0.05%, 0.1%, 0.2% or 0.4%) and treated with 6 weekly instillations of TMX-101, starting 2 weeks after transurethral resection of bladder tumor. Patients were evaluated weekly, and pharmacokinetic and pharmacodynamic parameters were measured. RESULTS: A total of 16 patients were included in the study with 4 per dose group. Two patients dropped out after instillation 2 in dose groups 1 and 2. Overall, 88 instillations were administered without serious adverse events. There were 118 adverse events, of which 84 were related to the study drug. All adverse events were mild or moderate and number or severity was not correlated with dose group. Of the related adverse events 70% were confined to the genitourinary tract and resolved without intervention. There was a dose dependent systemic uptake with low plasma levels up to dose group 3 (0.2%, 100 mg). Maximum plasma concentration in dose group 4 (0.4%, 200 mg) was 71.7 ng/ml. This is below plasma concentrations of 123 and 128 ng/ml without significant side effects measured in healthy volunteers after subcutaneous (30 mg) or oral intake (100 mg) of imiquimod, respectively. CONCLUSIONS: Intravesical treatment with TMX-101 is safe. The side effects are common but mild and mostly limited to the genitourinary tract. There is a low systemic uptake.
Assuntos
Aminoquinolinas/uso terapêutico , Carcinoma de Células de Transição/tratamento farmacológico , Carcinoma de Células de Transição/patologia , Terapia Neoadjuvante/métodos , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/patologia , Administração Intravesical , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Aminoquinolinas/efeitos adversos , Aminoquinolinas/farmacocinética , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Carcinoma de Células de Transição/mortalidade , Cistoscopia/métodos , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Seguimentos , Humanos , Imiquimode , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Países Baixos , Segurança do Paciente , Estudos Prospectivos , Medição de Risco , Fatores Sexuais , Taxa de Sobrevida , Resultado do Tratamento , Neoplasias da Bexiga Urinária/mortalidadeRESUMO
PURPOSE OF REVIEW: The management of nonmuscle-invasive bladder cancer is a challenge. Despite current guidelines, the treatment is suboptimal as illustrated by the high risk of recurrence and progression. Transurethral resection plays a pivotal role in the management of bladder cancer, but the quality varies dramatically. In this review, we discuss the latest developments that aim to improve the outcome of a transurethral resection such as photodynamic diagnosis, a second resection and adjuvant therapy. RECENT FINDINGS: The treatment of a bladder cancer patient can be improved, for example, with a standard second resection in a subset of the patients or the use of visual enhancement techniques. There is conflicting data on the clinical value of techniques like photodynamic diagnosis, as it does not always seem to translate into a better long-term outcome. Comparison of studies is difficult because of differences in patient selection and endpoints. Better classification in (personalized) risk categories may facilitate the treatment choice and prediction of the long-term outcome. SUMMARY: The outcome of bladder cancer patients can be improved. A good-quality transurethral resection of the bladder tumor is crucial and novel technological developments may improve the outcome, but they remain the subject of discussion.
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Assistência Perioperatória/métodos , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/cirurgia , Quimioterapia Adjuvante , Terapia Combinada , Humanos , Fotoquimioterapia , ReoperaçãoRESUMO
Bladder cancer comprises a heterogeneous group of tumors, the majority of which are non-muscle-invasive bladder cancer (NMIBC) at initial presentation. Low-risk bladder cancer--defined as pTa low-grade papillary tumors--is the type of NMIBC with the most favorable oncologic outcome. Although the risk of progression is less than 1% in 5 years, almost 15% will recur after 1 year, and 32% after 5 years. A complete transurethral resection, followed by an immediate single postoperative instillation of chemotherapy will reduce the risk of recurrence for the first 2 years. Follow-up cystoscopy is required to detect recurrence; in the vast majority of cases the recurrent tumor is of the same stage and grade as the primary tumor. The first follow-up visit, 3 months after surgery, is the most important in predicting risk of recurrence for the future. Recent developments in profiling urine and cancer tissue make it possible to better predict risk of progression and recurrence. In the future this profiling will play an important role in the timing and the choice of treatment, as well as guiding follow-up procedures.