Solares Ana M, Santana Agueda, Baladrón Idania, Valenzuela Carmen, González Carlos A, Díaz Alina, Castillo Dagnelia, Ramos Thelvia, Gómez Roberto, Alonso Daniel F, Herrera Luis, Sigman Hugo, Perea Silvio E, Acevedo Boris E, López-Saura Pedro
Gyneco-obstetric Hospital Clodomira Acosta Ferrales (National Reference Center for Cervical Cancer Research), Havana, Cuba.
BMC Cancer. 2009 May 13;9:146. doi: 10.1186/1471-2407-9-146.
Cervical cancer is now considered the second leading cause of death among women worldwide, and its incidence has reached alarming levels, especially in developing countries. Similarly, high grade squamous intraepithelial lesion (HSIL), the precursor stage for cervical cancer, represents a growing health problem among younger women as the HSIL management regimes that have been developed are not fully effective. From the etiological point of view, the presence of Human Papillomavirus (HPV) has been demonstrated to play a crucial role for developing cervical malignancies, and viral DNA has been detected in 99.7% of cervical tumors at the later stages. CIGB-300 is a novel cyclic synthetic peptide that induces apoptosis in malignant cells and elicits antitumor activity in cancer animal models. CIGB-300 impairs the Casein Kinase (CK2) phosphorylation, by targeting the substrate's phosphoaceptor domain. Based on the perspectives of CIGB-300 to treat cancer, this "first-in-human" study investigated its safety and tolerability in patients with cervical malignancies.
Thirty-one women with colposcopically and histologically diagnosed microinvasive or pre-invasive cervical cancer were enrolled in a dose escalating study. CIGB-300 was administered sequentially at 14, 70, 245 and 490 mg by intralesional injections during 5 consecutive days to groups of 7 - 10 patients. Toxicity was monitored daily until fifteen days after the end of treatment, when patients underwent conization. Digital colposcopy, histology, and HPV status were also evaluated.
No maximum-tolerated dose or dose-limiting toxicity was achieved. The most frequent local events were pain, bleeding, hematoma and erythema at the injection site. The systemic adverse events were rash, facial edema, itching, hot flashes, and localized cramps. 75% of the patients experienced a significant lesion reduction at colposcopy and 19% exhibited full histological regression. HPV DNA was negative in 48% of the previously positive patients. Long term follow-up did not reveal recurrences or adverse events.
CIGB 300 was safe and well tolerated. This is the first clinical trial where a drug has been used to target the CK2 phosphoaceptor domain providing an early proof-of-principle of a possible clinical benefit.
宫颈癌目前被认为是全球女性第二大死因，其发病率已达到惊人水平，尤其是在发展中国家。同样，高级别鳞状上皮内病变（HSIL）作为宫颈癌的前驱阶段，在年轻女性中也成为一个日益严重的健康问题，因为现有的HSIL治疗方案并不完全有效。从病因学角度来看，已证实人乳头瘤病毒（HPV）的存在在宫颈癌的发生中起关键作用，并且在晚期宫颈癌肿瘤中99.7%检测到病毒DNA。CIGB - 300是一种新型环状合成肽，可诱导恶性细胞凋亡并在癌症动物模型中引发抗肿瘤活性。CIGB - 300通过靶向底物的磷酸受体结构域来损害酪蛋白激酶（CK2）的磷酸化。基于CIGB - 300治疗癌症的前景，这项“首次人体”研究调查了其在宫颈恶性肿瘤患者中的安全性和耐受性。
31名经阴道镜和组织学诊断为微浸润或浸润前宫颈癌的女性被纳入剂量递增研究。将7 - 10名患者分为一组，连续5天通过病灶内注射依次给予CIGB - 300，剂量分别为14、70、245和490毫克。每天监测毒性直至治疗结束后15天，此时患者接受锥切术。还评估了数字阴道镜检查、组织学和HPV状态。
未达到最大耐受剂量或剂量限制性毒性。最常见的局部事件是注射部位疼痛、出血、血肿和红斑。全身不良事件有皮疹、面部水肿、瘙痒、潮热和局部痉挛。75%的患者在阴道镜检查中病变显著减少，19%表现出完全组织学消退。48%之前HPV DNA呈阳性的患者转为阴性。长期随访未发现复发或不良事件。
CIGB 300安全且耐受性良好。这是首次使用药物靶向CK2磷酸受体结构域的临床试验，为可能的临床益处提供了早期原理验证。
