背景:阿霉素和其他蒽环类药物是至关重要的癌症治疗药物。然而,它们与显著的心脏毒性有关,严重影响患者护理和限制剂量和使用。先前的研究表明,低一氧化碳(CO)浓度可防止阿霉素毒性。然而,传统的CO输送方法对日常给药提出了复杂的挑战,如剂量和毒性。为了应对这些挑战,我们开发了一种含有CO的新型口服液体药物(HBI-002),可以很容易地由接受阿霉素治疗的癌症患者自行服用,导致CO通过上胃肠道递送。
结果:在存在和不存在肺癌或乳腺癌的多柔比星心脏毒性的小鼠模型中测试了HBI-002。小鼠在施用阿霉素之前每天两次接受HBI-002,并且经历了从约1%至7%的基线增加的碳氧血红蛋白水平。与安慰剂对照相比,用HBI-002处理的小鼠的心脏组织的CO浓度增加了6.3倍,细胞保护酶血红素加氧酶-1的表达更高。在急性和慢性阿霉素毒性情况下,HBI-002保护心脏免受心脏毒性作用,包括限制组织损伤和心功能不全,提高生存率。此外,HBI-002并没有损害阿霉素在减少肿瘤体积方面的功效,而是增强乳腺癌4T1癌细胞对阿霉素的敏感性,同时保护心脏功能。
结论:这些发现强烈支持使用HBI-002作为心脏保护剂,维持阿霉素癌症治疗的治疗益处,同时减轻心脏损伤。
BACKGROUND: Doxorubicin and other anthracyclines are crucial cancer treatment drugs. However, they are associated with significant cardiotoxicity, severely affecting patient care and limiting dosage and usage. Previous studies have shown that low carbon monoxide (CO) concentrations protect against doxorubicin toxicity. However, traditional methods of CO delivery pose complex challenges for daily administration, such as dosing and toxicity. To address these challenges, we developed a novel oral liquid drug product containing CO (HBI-002) that can be easily self-administered by patients with cancer undergoing doxorubicin treatment, resulting in CO being delivered through the upper gastrointestinal tract.
RESULTS: HBI-002 was tested in a murine model of doxorubicin cardiotoxicity in the presence and absence of lung or breast cancer. The mice received HBI-002 twice daily before doxorubicin administration and experienced increased carboxyhemoglobin levels from a baseline of ≈1% to 7%. Heart tissue from mice treated with HBI-002 had a 6.3-fold increase in CO concentrations and higher expression of the cytoprotective enzyme heme oxygenase-1 compared with placebo control. In both acute and chronic doxorubicin toxicity scenarios, HBI-002 protected the heart from cardiotoxic effects, including limiting tissue damage and cardiac dysfunction and improving survival. In addition, HBI-002 did not compromise the efficacy of doxorubicin in reducing tumor volume, but rather enhanced the sensitivity of breast 4T1 cancer cells to doxorubicin while simultaneously protecting cardiac function.
CONCLUSIONS: These findings strongly support using HBI-002 as a cardioprotective agent that maintains the therapeutic benefits of doxorubicin cancer treatment while mitigating cardiac damage.