scholarly journals Antitumor Efficacy of Intravesical BCG, Gemcitabine, Interferon-α and Interleukin-2 as Mono- or Combination-Therapy for Bladder Cancer in an Orthotopic Tumor Model

2011 ◽  
Vol 5 ◽  
pp. CMO.S7658 ◽  
Author(s):  
Zhengwen Xiao ◽  
Erich Hanel ◽  
Allan Mak ◽  
Ronald B. Moore
Keyword(s):  
Bladder Cancer ◽  
Treatment Response ◽  
Low Dose ◽  
Interleukin 2 ◽  
Tumor Model ◽  
Interferon Α ◽  
High Dose ◽  
Female Rat ◽  
Rat Tumor Model ◽  
Intravesical Bcg

Objective To reduce adverse effects and improve efficacy of intravesical BCG for bladder cancer, alternative treatment options were investigated in an orthotopic rat tumor model. Methods Superficial bladder cancer was established in syngeneic female rat bladders by instillation of AY-27 cells. Animals were randomly assigned to treatment groups including dose escalation of intravesical BCG with or without interferon-α (IFN-α) or interleukin-2 (IL-2); or graded doses of gemcitabine alone; or BCG plus gemcitabine. Treatments were given twice weekly for 3 weeks. Rats in control groups received saline instillations. Treatment response was monitored by animals’ well-being, survival days, tumor growth inhibition, and histological examination at necropsy. Results Rats receiving monotherapy with intravesical BCG, gemcitabine, or IFN-α, attained significantly better survival and tumor reduction compared with control ( P = 0.002; 0.001; 0.002, respectively, Log-rank Test). A dose-dependent treatment response was observed in animals with established bladder tumor receiving escalated BCG instillations. Only high-dose BCG significantly improved animal survival. Although high-dose BCG plus gemcitabine or IFN-α did not increase benefit over monotherapies, low-dose BCG plus IL-2 did show improved efficacy ( P = 0.01). Conclusion Intravesical monotherapies with gemcitabine and IFN-α were as effective as BCG for treatment of early non-muscle-invasive urothelial bladder cancer in this immune competent rat model. Combining these agents with high-dose BCG did not further increase efficacy. However, combining low-dose BCG with IL-2 enhanced BCG effectiveness.

scholarly journals Phase I Trial of Sequential Low-Dose 5-Aza-2′-Deoxycytidine Plus High-Dose Intravenous Bolus Interleukin-2 in Patients with Melanoma or Renal Cell Carcinoma

2006 ◽  
Vol 12 (15) ◽  
pp. 4619-4627 ◽  
Author(s):  
Jared A. Gollob ◽  
Catherine J. Sciambi ◽  
Bercedis L. Peterson ◽  
Tina Richmond ◽  
Monica Thoreson ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Phase I ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Phase I Trial ◽  
Low Dose ◽  
Interleukin 2 ◽  
High Dose ◽  
Intravenous Bolus

scholarly journals Intravesical High Dose BCG Tokyo and Low Dose BCG Tokyo with GMCSF+IFN α Induce Systemic Immunity in a Murine Orthotopic Bladder Cancer Model

Biomedicines ◽  
2021 ◽  
Vol 9 (12) ◽  
pp. 1766
Author(s):  
Sin Mun Tham ◽  
Juwita N. Rahmat ◽  
Edmund Chiong ◽  
Qinghui Wu ◽  
Kesavan Esuvaranathan ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Bladder Cancer ◽  
Low Dose ◽  
Bladder Cancer Cell Line ◽  
High Dose ◽  
Cytokine Gene ◽  
Systemic Immunity ◽  
Bcg Therapy ◽  
Cytokine Gene Therapy

This study evaluates a short therapy schedule for bladder cancer using BCG Tokyo. BCG Tokyo was evaluated in vitro using bone marrow derived dendritic cells, neutrophils, RAW macrophages and the murine bladder cancer cell line, MB49PSA, and compared to other BCG strains. BCG Tokyo > BCG TICE at inducing cytokine production. In vivo, high dose (1 × 107 colony forming units (cfu)) and low dose (1 × 106 cfu) BCG Tokyo with and without cytokine genes (GMCSF + IFNα) were evaluated in C57BL/6J mice (n = 12–16 per group) with orthotopically implanted MB49PSA cells. Mice were treated with four instillations of cytokine gene therapy and BCG therapy. Both high dose BCG alone and low dose BCG combined with cytokine gene therapy were similarly effective. In the second part the responsive groups, mice (n = 27) were monitored by urinary PSA analysis for a further 7 weeks after therapy cessation. More mice were cured at day 84 than at day 42 confirming activation of the immune system. Cured mice resisted the re-challenge with subcutaneous tumors unlike naïve, age matched mice. Antigen specific T cells recognizing BCG, HY and PSA were identified. Thus, fewer intravesical instillations, with high dose BCG Tokyo or low dose BCG Tokyo with GMCSF + IFNα gene therapy, can induce effective systemic immunity.

scholarly journals Relationship between chorionic gonadotropin immunomodulating effects and the initial functional activity of the splenocytes mediating the adoptive immune response

1993 ◽  
Vol 39 (1) ◽  
pp. 54-57 ◽  
Author(s):  
S. V. Shirshev ◽  
N. N. Kevorkov
Keyword(s):  
Immune Response ◽  
Chorionic Gonadotropin ◽  
Functional Activity ◽  
Low Dose ◽  
Interleukin 2 ◽  
Prostaglandin Synthesis ◽  
High Dose ◽  
Transfer System ◽  
Male Mice ◽  
Stimulation Of

CBA and (СВАхC57BL/6) F1 male mice were used in experiments. One hour incubation of splenocytes with chorionic gonadotropin in doses 10 or 50 MU/ml statistically significantly reduced the count of antibody-producing cells detectable in the syngeneic transfer system. Addition of conA or recombinant human interleukin 2 to the splenocyte culture did not alter the processes of the formation of antibodyproducing cells. Addition of chorionic gonadotropin simultaneously with conA resulted in discontinuation of the immunosuppression induced by a low hormone dose, whereas 50 MU/ml of chorionic gonadotropin in the presence of conA had a marked immunodepressant effect. Combination of interleukin 2 with chorionic gonadotropin lead either to immunosuppression cessation (10 MU/ml) or to more than twofold stimulation of the adoptive immune response (50 MU/ml). Voltaren a cycloxygenase inhibitor, was used in some experiments to elucidate the degree of endogenic prostaglandin relationships with the mechanisms of chorionic gonadotropin immunomodulating effects. Cycloxygenase activity was found to be related to the immunosuppressive effect of chorionic gonadotropin low dose, whereas the costimulating effect of a high dose of the hormone in the presence of interleukin 2 was unrelated to endogenic prostaglandin synthesis.

scholarly journals Increased thromboxane mediates the adverse renal effects of interleukin-2 in rats.

1994 ◽  
Vol 4 (9) ◽  
pp. 1701-1710
Author(s):  
D Rubinger ◽  
E Cohen ◽  
Y Haviv ◽  
J Bernheim ◽  
E Shiloni ◽  
...  
Keyword(s):  
Body Weight ◽  
Urinary Excretion ◽  
Low Dose ◽  
Combined Therapy ◽  
Interleukin 2 ◽  
Chronic Administration ◽  
Urinary Sodium Excretion ◽  
Metabolic Effects ◽  
High Dose ◽  
Sodium And Potassium

The capillary leak syndrome with decreased GFR and renal water and sodium retention after recombinant interleukin-2 (IL-2) administration may arise from endothelial activation via an increase in prostaglandin synthesis. This study was undertaken to better define the role of the prostaglandin system in the renal and metabolic effects of IL-2 administration in rats. The chronic administration of IL-2 (100,000 U/kg, thrice daily, ip) resulted in a significant increase in body weight, a decrease in GFR and in the urinary excretion of sodium and potassium, and an increase in the urinary excretion of thromboxane (TXB2). After combined IL-2 and low-dose indomethacin (1.7 mg/kg per day po), a significant decrease in body weight with normalization of GFR, of the urinary excretion of Na, and of urinary TXB2 was noted in animals receiving combined therapy as compared with those receiving IL-2 alone. In contrast, high-dose indomethacin administration (33.3 mg/kg po for the last 3 days of the study) was associated with a further decrease in GFR, enhancement of the sodium and potassium retention, and suppression of prostaglandin E2 excretion. The administration of the thromboxane receptor antagonist SQ 29548 in IL-2-treated rats led to a reversal of the fall in GFR induced by the lymphokine without significant changes in urinary sodium excretion. These results support the hypothesis that thromboxane is an important mediator of the renal and systemic effects of IL-2. These effects are reversed at least partly by low-dose indomethacin, which selectively suppresses thromboxane A2 (TXA2) synthesis, or by TXA2 receptor antagonism.

Low-dose versus standard-dose gemcitabine infusion and cisplatin for patients with advanced bladder cancer: A randomized phase II trial.

2011 ◽  
Vol 29 (7_suppl) ◽  
pp. 266-266 ◽  
Author(s):  
H. Khaled ◽  
F. Abu-Taleb ◽  
R. Haggag ◽  
A. Zekri
Keyword(s):  
Bladder Cancer ◽  
Disease Progression ◽  
Phase Ii ◽  
Low Dose ◽  
Response Rate ◽  
Phase Ii Trial ◽  
High Dose ◽  
Prolonged Infusion ◽  
Significant Difference ◽  
Gemcitabine And Cisplatin

266 Background: Bladder carcinoma is the foremost oncologic problem in Egypt. Prolonged infusion of gemcitabine and cisplatin is an effective treatment for advanced bilharzial-related bladder cancer based on a previously published phase II trial. Methods: To compare efficacy and safety of both prolonged infusion and standard gemcitabine-cisplatin combination, this phase II randomized study of 60 untreated patients with stage III/IV bladder cancer was conducted. Patients were randomized to receive either gemcitabine (250 mg/m2) 6-hour infusion on days 1 and 8, and cisplatin (70 mg/m2) on day 2 every 21-day cycle (Arm1) or gemcitabine (1,250 mg/m2) 30-min infusion on days 1 and 8, and cisplatin (70 mg/m2) on day 2 every 21-day cycle (Arm 2). Results: The 47 males and 13 females had a median age of 60 years (range 40-73 years). A total of 44 patients had transitional cell, 12 had squamous cell, and 4 had undifferentiated cell carcinoma. Among the 53 evaluable patients (26 patients in arm1 and 27 patients in arm 2), complete response rate was achieved in 19.3% (5/26 patients of arm 1) and 7.4% (2/27 patients of arm 2). Eight patients in arm 1 (30.7%) and 7 patients (25.9%) in arm 2 had partial response on therapy. Thus the overall response rate of patients in arm1 and arm 2 was 50% (13/26 patients) and 33.3% (9/27patients), respectively (p = 0.21). No significant difference in median time to disease progression (6.7 months versus 7.9 months, p = 0.42), median survival (9.7 months versus 8.8 months, p = 0.3), and 1-year survival (27% versus 6%, p = 0.3) was detected between arms 1 and 2, respectively. No treatment- related deaths occurred. Main hematologic and nonhematologic toxicities were similar in both arms with no statistically significant differences. Conclusions: In the treatment of advanced bilharzial bladder cancer, gemcitabine in low dose and prolonged infusion in combination with cisplatin is not inferior to high-dose short infusion gemcitabine and cisplatin in terms of overall survival, time to disease progression, and response rates with favorable toxicity profile and less financial costs. No significant financial relationships to disclose.

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