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。由于其易于接近的位置和相对早期的诊断，膀胱癌是致命性最低的癌症之一，在美国约有54万幸存者。在临床上，>80%的膀胱肿瘤局限于器官，临床上分为两组。最常见的是非肌肉侵犯性肿瘤，约占病例的70-80%。这一组是通过手术，加上新的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滴入膀胱。复发是常见的，发生在40%至80%的患者中。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，肌肉浸润性肿瘤，通过部分或完全膀胱切除术（切除膀胱）进行治疗，这存在显著的风险，老年患者的耐受性较差。 膀胱内治疗最常用的化疗药物是丝裂霉素C（MMC）和多柔比星。通过一系列临床前和临床研究，我们的研究小组已经确定这些药物的疗效受到两个因素的限制：药物输送到肿瘤和低化疗敏感性（特别是对于更具侵袭性的肿瘤）。接下来，我们确定了一种方法，使用药代动力学（PK）干预，以最大限度地将MMC输送到非肌肉侵入性膀胱肿瘤。在一项多中心、随机III期试验中对该方法进行了测试;结果证实了我们的假设，即改善药物递送显著提高了5年无复发率（从23.5%提高到42.6%）。这些数据还表明，需要一种新的药物输送方法用于剩余的患者，即那些患有肌肉侵入性肿瘤的患者，这些患者不能通过膀胱内治疗进行充分管理。 该R43申请提出了一种通过替代给药途径的新的药物递送方法：膀胱内注射MMC和苏拉明的控释制剂（CRF），使得治疗活性药物水平被递送至更深的组织。苏拉明用于增强人类肿瘤对MMC的敏感性2至3倍。两个目的是（a）开发MMC和苏拉明的生物相容性聚合CRF和（B）进行载药CRF的体内评价以确定使用膀胱内CRF治疗更深肿瘤的可行性。在证明可行性后，我们将在稍后的R44项目中研究该组合在荷瘤动物中的治疗功效（例如，具有天然存在的膀胱肿瘤的狗），为最终的临床评价做准备。这个R43项目有可能导致一种新的治疗方式，并显着改善膀胱癌的管理，而疾病仍然局限于膀胱。鉴于这些患者的终身医疗保健费用极高（按2003年美元计算超过100亿美元），另一个潜在的好处是成本控制。

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.