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

描述(申请人提供)：膀胱癌是美国第四大常见癌症。由于其地理位置便利，诊断相对较早，膀胱癌是致命性最低的癌症之一，美国约有54万名幸存者。在临床表现上，80%的膀胱肿瘤是器官受限的，临床上分为两组。最常见的是非肌肉侵袭性肿瘤，约占病例的70-80%。这组患者接受手术治疗，外加新生或佐剂膀胱内免疫治疗或化疗。膀胱内治疗包括通过留置导尿管将药物溶液注入膀胱。复发很常见，40%到80%的患者会复发。10%到20%的复发伴随着分级和/或分期进展(包括更致命的转移性疾病)。第二组是肌肉侵袭性肿瘤，采用部分或完全膀胱切除术(切除膀胱)，风险很大，老年患者不能很好地耐受。最常用的膀胱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：对肿瘤的药物输送不足和低化疗敏感性(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)干预来最大化MMC对非肌肉侵袭性膀胱肿瘤的传递的方法。这种方法在一项多中心、随机的III期试验中进行了测试；结果证实了我们的假设，即改善药物输送显著提高了5年无复发率(从23.5%提高到42.6%)。这些数据还表明，需要为剩余的患者提供新的药物输送方法，这些患者患有肌肉侵袭性肿瘤，这些患者没有得到充分的膀胱内治疗。这项R43申请提出了一种新的给药方法，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)，以便将治疗活性药物水平传递到更深的组织。苏拉明用于将人类肿瘤对MMC的敏感性提高2-3倍。这两个目的是(A)开发MMC和苏拉明的生物相容性聚合物CRF和(B)对载药CRF进行体内评价，以确定使用膀胱内CRF治疗深层肿瘤的可行性。在证明可行性后，我们将在稍后的R44项目中研究联合应用于荷瘤动物(例如患有自然发生的膀胱肿瘤的狗)的疗效，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，并显著改善膀胱癌的管理，而疾病仍局限于膀胱癌。鉴于这些患者的终生保健成本极高(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。 公共卫生相关性：这个R43项目有可能导致一种新的治疗方式，并在膀胱癌仍局限于膀胱的情况下显著改善膀胱癌的管理。鉴于这些患者的终生保健成本极高(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. PUBLIC HEALTH RELEVANCE: 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.