The immunosuppression that is known to occur as a result of cancer chemotherapy application is widely considered to be a harmful side effect. This side effect not only poses a risk of infection but also has the potential to significantly reduce the overall quality of life for patients undergoing this treatment. Hence, in this blog, I would like to share the study, “ Influence of Modified Fucoidan and Related Sulfated Oligosaccharides on Hematopoiesis in Cyclophosphamide-Induced Mice” by Natalia Yu Anisimova et al.

Cyclophosphamide (CPh) is an alkylating agent that is currently employed for the therapeutic management of various forms of malignant neoplasms. Acute neutropenia, lymphopenia, erythropenia, and thrombocytopenia are the predominant side effects of CPh.

The study provides a detailed report on the analysis of modified fucoidan (M-Fuc), as well as the synthetic octasaccharide (OS) and disaccharide (DS), in terms of their effectiveness as hematopoietic stimulators in a murine CPh immunosuppression model. In addition, they have discovered a linear sulfated (1→3)-α-l-fucan M-Fuc. This fucan is prepared through chemical modification of fucoidan, which is isolated from the brown alga Chordaria flagelliformis. They have conducted a study on cyclophosphamide immunosuppression in mice, where they investigated the effects of two structurally related synthetic sulfated oligosaccharides. These oligosaccharides were found to stimulate hematopoiesis.

In order to assess their impact on hematopoiesis, we evaluated the effects of compounds M-Fuc, OS, and DS using a CPh-induced immunosuppression model in mice. As a control, we administered recombinant granulocyte colony-stimulating factor r G-CSF (Leicyta). Animals in an intact state were utilized as positive controls, and measurements of white and red blood cells (WBC, RBC), platelets, and hemoglobin levels were conducted as well.

The CPh injection exhibited a 2.9-fold decline in white blood cell concentration, a 1.7-fold decline in red blood cell concentration, a 1.5-fold decline in hemoglobin concentration, and a 1.4-fold rise in platelet levels. Following treatment, the subsequent use of rG-CSF exhibited a tendency to restore RBC, hemoglobin, and platelet levels to normal. For treatment with fucoidan M-Fuc and disaccharide DS, the most significant effects were observed in the presence of octasaccharide OS, even exceeding those of rG-CSF. The concentrations of white blood cells, red blood cells, and hemoglobin in the CPh + OS group were found to have recovered to levels similar to those of the positive control. Platelet levels remained elevated.

A more detailed analysis of lymphocyte subpopulations demonstrated a significant decline in a particular subset of CD3+CD4+ cells after CPh treatment. A considerable reduction in cell count prompted the implementation of OS injection, resulting in the restoration of the CD4+/CD8+ index to the same level as the control group (1.93 ± 0.19). Conversely, the utilization of rG-CSF displayed a similar tendency, albeit with a lesser degree of efficiency. The findings of this study indicate that the molecular structure of the compound under investigation, which is related to fucoidan, plays a key role in determining its effectiveness in stimulating hematopoiesis in mice with CPh-induced myelosuppression.

Synthetic octasaccharide OS was shown to be the most active sample capable of restoring the levels of white blood cells, red blood cells, and hemoglobin, as well as the absolute numbers of neutrophils, monocytes, and lymphocytes to intact control levels. The experiments did not show any significant effect of the low molecular weight modified fucoidan M-Fuc and the synthetic disaccharide DS, suggesting that parameters such as sulfation degree and molecular weight are crucial for this specific activity.

Next, they found that introducing CPh did not lead to a decrease in the functional activity of blood granulocytes released when bacterial capture rates were high. Observations indicate a marginal decline in the rate of phagocytic activity within the CPh + r G-CSF group, as compared to the intact control. This phenomenon likely occurred as a result of the recruitment of youthful cells from the bone marrow. On the other hand, the CPh + OS group demonstrated an increase in phagocytic activity of granulocytes, as opposed to the control group.

Further investigation was conducted to clarify the impact of the test compound on bone marrow cells. Following the treatment with CPh, there was an observed reduction in the quantity of CD34+ progenitor cells, as depicted in Figure 1.

Bone marrow cell cycle analysis revealed that OS stimulates hematopoietic progenitor cell proliferation approximately three times more effectively than rG-CSF. The number of these cells in the CPh + OS group was also approximately 1.5 times higher than in the r G-CSF group (Figure 1). Additionally, the results depicted in Figure 2 clearly demonstrate the ability of OS to effectively stimulate the repair of splenic structures following myelosuppression induced by CPh.

Thus, the hematopoiesis-stimulating effects of fully sulfated synthetic octasaccharide OS are greater than those of G-CSF. The quantity of hematopoietic progenitor cells is present in the bone marrow. The results obtained from this study can be regarded as a solid foundation for the development of drugs aimed at treating and preventing immunosuppressive complications. In addition, the utilization of OS derivatives could be used to construct hybrid systems that exhibit stronger biological effects.

Source: Mar Drugs. 2018 Sep; 16(9): 333.. doi: 10.3390/md16090333