Intra-bladder MMC & suramin for nonmuscle-invading & locally advanced bladder ca

描述（由申请人提供）：膀胱癌是美国第四大常见癌症。由于膀胱癌的位置容易接近和相对较早的诊断，它是最不致命的癌症之一，在美国约有54万幸存者。膀胱肿瘤首发时，bbb80 %为器官局限型，临床分为两组。最常见的是非肌肉侵袭性肿瘤，约占病例的70-80%。本组采用手术加新或辅助膀胱内免疫治疗或化疗。膀胱内治疗包括通过留置导管将药物溶液注入膀胱。复发是常见的，发生在40%至80%的患者。10%至20%的复发伴有分级和/或分期进展（包括更致命的转移性疾病）。第二组，肌肉侵入肿瘤，通过部分或完全膀胱切除术（膀胱切除）来治疗，这有很大的风险，老年患者不能很好地耐受。最常用的囊内化疗药物是丝裂霉素C （MMC）和阿霉素。通过一系列临床前和临床研究，我们的团队已经确定这些药物的疗效受到两个因素的限制：肿瘤给药不足和低化学敏感性（特别是对更具侵袭性的肿瘤）。接下来，我们确定了一种使用药代动力学（PK）干预的方法，以最大限度地将MMC递送到非肌肉侵入性膀胱肿瘤。该方法在一项多中心随机III期试验中得到验证；结果证实了我们的假设，即改善给药方式可显著提高5年无复发率（从23.5%提高到42.6%）。这些数据还表明，需要一种新的药物给药方法来治疗剩余的患者，那些患有肌肉侵袭性肿瘤的患者，他们不能通过膀胱内治疗得到充分的治疗。这项R43申请提出了一种新的药物递送方法，通过另一种给药途径：膀胱内注射MMC和苏拉明的控释制剂（CRF），从而将治疗活性药物水平递送到更深的组织。苏拉明用于将人类肿瘤对MMC的敏感性提高2- 3倍。两个目标是：(a)开发MMC和苏拉明的生物相容性聚合物CRF， (b)对载药CRF进行体内评估，以确定使用膀胱内CRF治疗更深层次肿瘤的可行性。在证明可行性后，我们将在后期的R44项目中研究该组合在荷瘤动物（如自然发生膀胱肿瘤的狗）中的治疗效果，为最终的临床评估做准备。这个R43项目有可能导致一种新的治疗方式，并在疾病仍局限于膀胱时显著改善膀胱癌的治疗。鉴于这些患者的终生保健费用极高（按2003年美元计算超过100亿美元），另一个潜在好处是成本控制。

DESCRIPTION (provided by applicant): Bladder cancer is the fourth most common cancer in the US. Due to its easily accessible location and relatively early diagnosis, bladder cancer is one of the least lethal cancers and there are ~540,000 survivors in the US. At presentation, >80% of bladder tumors are organ-confined, separated clinically into two groups. The most common group is the nonmuscle-invading tumors, accounting for about 70-80% of cases. This group is managed by surgery, plus neo- or adjuvant intravesical immunotherapy or chemotherapy. Intravesical therapy involves instilling a drug solution into the bladder through an indwelling catheter. Recurrence is common and occurs in 40 to 80% of patients. Between 10 to 20% of recurrences are accompanied by grade and/or stage progression (including the more fatal metastatic disease). The second group, the muscle-invading tumors, is managed by partial or complete cystectomy (removal of bladder), which presents significant risks and is not well-tolerated by older patients. The most commonly used chemotherapeutic agents for intravescial therapy are mitomycin C (MMC) and doxorubicin. Through a series of preclinical and clinical studies, our group has established that the efficacy of these agents is limited by two factors: inadequate drug delivery to tumors and low chemosensitivity (especially for the more aggressive tumors). Next, we identified a method that uses pharmacokinetic (PK) interventions to maximize the MMC delivery to nonmuscle-invading bladder tumors. This method was tested in a multi-center, randomized phase III trial; the results confirm our hypothesis that improving the drug delivery significantly improves the 5-yr recurrence-free rate (from 23.5% to 42.6%). These data also indicate that a new drug delivery approach is needed for the remaining patients, those with muscle-invading tumors, who are not adequately managed by intravesical therapy. This R43 application proposes a new drug delivery approach via an alternative administration route: intra-bladder injection of controlled release formulations (CRF) of MMC and suramin, such that therapeutic active drug levels are delivered to deeper tissues. Suramin is used to enhance the sensitivity of human tumors to MMC by 2- to 3-fold. The two aims are to (a) develop biocompatible polymeric CRF of MMC and suramin and (b) conduct in vivo evaluation of the drug-loaded CRF to determine the feasibility of using intra-bladder CRF to treat deeper tumors. Upon demonstration of feasibility, we will investigate, in the later R44 project, the therapeutic efficacy of the combination in tumor-bearing animals (e.g., dogs with naturally occurring bladder tumors), in preparation for the eventual clinical evaluation. This R43 project has the potential to lead to a new treatment modality and significantly improve the management of bladder cancer while the disease is still localized in the bladder. Given the extremely high lifetime health care costs for these patients (over $10 billion in 2003 dollars), an additional potential benefit is cost containment.