Preclinical characteristics of siRNA duplexes as targeted adjuvants in malignant growth

Background. Small or short double-stranded interfering RNAs (siRNAs, small interfering RNAs) 20–25 nucleotides long are known to be able to target block uncontrolled malignant proliferation. As target genes, apoptosis inhibitors are considered, including the cellular glycoprotein CD47 (cluster of differentiation 47), and genes of the replicative complex that regulate the cell cycle in the S phase. This determines the relevance of the study in tumor models of siRNAs aimed at these targets as adjuvants.

Aim. To evaluate the antiproliferative effects of novel siRNAs as adjuvants for immune-/chemotherapy in human colorectal and renal cancer models.

Materials and methods. SiRNA/antiCD47 and two-component siRNA antiMSM4/antiLIVIN were developed at the Research Centre for Medical Genetics and studied in lipid dispersion for intravenous (IV) administration. Preclinical models – subcutaneous xenographs of RTK-8 colon cancer and human kidney cancer Rpoch-1/CD47, Balb/c nude mice were obtained from the N.N. Blokhin National Medical Research Center of Oncology. In the adjuvant mode, siRNA/antiCD47 was studied in combination with activated human macrophages (AM), siRNA antiMSM4/antiLIVIN (1:1) – with cyclic-dependent cytostatic oxaliplatin (OXP). Administration regimens are justified earlier. Efficacy parameters and criteria (treatment/control (T/C) ≤42 %), tolerability of effects and statistical analysis at p <0.05 are standard for experimental cancer therapy. Laboratory manipulations are regulated by the current recommendations of the Ministry of Health of the Russia.

Results. The siRNA/anti-CD47 + AM regimen was practically ineffective at Rpoch-1/CD47, T/C = 45 % (p >0.05). The antiMCM4/antiLIVIN + 24 h siRNA regimen on an OXP-insensitive RTK-8 showed a significant adjuvant effect against cytostatic, T/C = 33–21 % versus T/C_min = 49 % (p ≤0.05). Both combinations were tolerable.

Conclusion. Preclinical study showed the controversy of the assumption about the possibility of adjuvant use of siRNA/antiCD47 with AM and the promise of antiMSM4/antiLIVIN siRNA on low-sensitivity to cycle-dependent OXR in human colon cancer with the possibility of cell cycle synchronization.