A clinical trial is conducted to assess the effectiveness of a novel formulation of cisplatin for treating advanced non-small cell lung cancer. Study participants are randomly assigned to 2 different cisplatin-based chemotherapy regimens. Subjects in the control arm are administered conventional cisplatin chemotherapy, whereas those in the experimental arm are given a formulation of cisplatin encapsulated in liposomes coated with anti-epidermal growth factor receptor (EGFR) antibodies. Patients in the experimental group are found to have a statistically significant decrease in residual tumor burden compared with those in the control group. The incidence of adverse effects was also lower in the experimental group. Compared to conventional cisplatin chemotherapy, the new formulation is most likely to have which of the following effects?

Question

A clinical trial is conducted to assess the effectiveness of a novel formulation of cisplatin for treating advanced non-small cell lung cancer.  Study participants are randomly assigned to 2 different cisplatin-based chemotherapy regimens.  Subjects in the control arm are administered conventional cisplatin chemotherapy, whereas those in the experimental arm are given a formulation of cisplatin encapsulated in liposomes coated with anti-epidermal growth factor receptor (EGFR) antibodies.  Patients in the experimental group are found to have a statistically significant decrease in residual tumor burden compared with those in the control group.  The incidence of adverse effects was also lower in the experimental group.  Compared to conventional cisplatin chemotherapy, the new formulation is most likely to have which of the following effects?

Quizplus · Accepted Answer

11ec160b_3c2f_a7b1_9249_f74adda96bad_MD0001_00 Platinum-based chemotherapy agents (eg, cisplatin) are widely used as a first-line treatment for many solid tumors, including non-small cell lung cancer. These agents disrupt DNA replication and have substantial cytotoxicity against rapidly proliferating cells. Despite their efficacy in killing tumor cells, their use is limited by severe adverse effects (eg, nephrotoxicity, ototoxicity, myelosuppression) that occur due to accumulation within normal tissues (ie, off-target effects). Methods that provide targeted delivery to the tumor site can help minimize toxicity and optimize drug response. In this example, cisplatin is encapsulated in liposomes, forming a nanoparticle cage that traps the drug and limits its interaction with normal cells. The addition of anti-epidermal growth factor receptor (anti-EGFR) antibodies on the liposome surface results in an antibody-drug conjugate, allowing the encapsulated drug complex to selectively bind to tumor cells expressing high levels of EGFR, which is often overexpressed in non-small cell lung cancer. Once bound, the antibody-drug complex is internalized and degraded, releasing the free drug into the cytoplasm and causing targeted cell death. (Choice A) Overexpression of drug efflux pumps (eg, P-glycoprotein) by cancer cells is a major cause of chemotherapy resistance. Efflux pump inhibitors can decrease drug excretion from tumor cells and potentiate the effects of chemotherapeutic agents. (Choice B) Many cancers create an immunosuppressive microenvironment that prevents the immune system from effectively killing tumor cells. An enhanced cytotoxic T-cell response against tumor cells occurs with the use of immune checkpoint inhibitors (eg, PD-1 or CTLA-4 receptor inhibitors) that help prevent T-cell exhaustion. (Choice C) Desmoplasia (ie, reactive growth of fibrous connective tissue) occurs in response to certain tumors (eg, breast, pancreatic carcinoma). The dense fibrotic tissue acts as a molecular sieve, decreasing the penetration of chemotherapeutic agents. Chemoresistance is more likely to occur with larger drug complexes; in this case, the new liposomal formulation will be much larger than individual cisplatin molecules, resulting in decreased desmoplastic penetration. (Choice D) Increased expression of vascular endothelial growth factor (VEGF) within tumors stimulates blood vessel growth, facilitating tumor expansion and increasing the potential for metastasis. Anti-VEGF antibodies (eg, bevacizumab) bind VEGF and inhibit tumor-induced angiogenesis. Although EGFR stimulation also plays a role in angiogenesis, in this case, the anti-EFGR antibodies are used for targeting purposes and may not necessary inhibit the EFGR receptor (antibodies can be stimulatory, inhibitory, or have no signaling effect depending on the attachment site). Educational objective: Antibody-drug conjugates improve drug efficacy and minimize toxicity by allowing conventional chemotherapeutic agents (eg, cisplatin) to selectively target and kill cancer cells while sparing healthy cells (ie, targeted delivery).

A Clinical Trial Is Conducted to Assess the Effectiveness of a Novel