Doxorubicin-polyglycerol-nanodiamond conjugate is a cytostatic agent that evades chemoresistance and reverses cancer-induced immunosuppression in triple-negative breast cancer

Background Triple negative breast cancer (TNBC) has the poorest prognosis of all breast cancer subtypes and is one of the most fatal diseases for women. Combining cytotoxic chemotherapy with immunotherapy has shown great promise for TNBC treatment. However, chemotherapy often leads to the development of chemoresistance and severe systemic toxicity compromising the immune functions that are crucial to anti-TNBC immune therapy. Tumor-induced immunosuppression also poses a great hindrance to efficacious anti-TNBC immunotherapy. Nanomedicine holds great promise to overcome these hurdles. Results Doxorubicin-polyglycerol-nanodiamond conjugate (Nano-DOX) was firstly found to be a cytostatic agent to the 4T1 cells and displayed a lower apparent therapeutic potency than DOX. However, the tumor-bearing animals, particularly some key immune cells thereof, showed good tolerance of Nano-DOX as opposed to the severe toxicity of DOX. Next, Nano-DOX did not induce significant upregulation of P-gp and IL-6, which were demonstrated to be key mediators of chemoresistance to DOX in the 4T1 cells. Then, Nano-DOX was shown to downregulate tumor-derived granulocyte-colony stimulating factor (G-CSF) and suppresses the induction and tissue filtration of myeloid-derived suppressor cells (MDSCs) that are the principal effectors of cancer-associated systemic immunosuppression. Nano-DOX also alleviated the phenotype of MDSCs induced by 4T1 cells. Finally, Nano-DOX induced the 4T1 cells to emit damage associated molecular patterns (DAMPs) that stimulated the tumor immune microenvironment through activating key immune effector cells involved in anti-tumor immunity, such as macrophages, dendritic cells and lymphocytes in the tumor tissue. Conclusions Nano-DOX is a cytostatic agent with good host tolerance which is capable of evading chemoresistance and reversing cancer-induced immunosuppression both at the systemic level and in the tumor microenvironment in TNBC. Our work presents Nano-DOX as an interesting example that a chemotherapeutic agent in nano-form may possess distinct biochemical properties from its free form, which can be exploited to join chemotherapy with immunotherapy for better treatment of cancer.

ANTIBODY-DRUG CONJUGATES FOR TARGETED CANCER THERAPY

Monoclonal antibody (MAB) conjugates with cytostatic agents (ADC) are intended for selective delivery of a cytostatic agent to a tumor cell. Three ADC have been approved for clinical use (gemtuzumab ozogamicin, brentuximab vedotin, trastuzumab-DM1); a few dozens of other ADC are undergoing clinical trials. Several derivatives of natural substances (antibiotics and inhibitors of microtubules) having a high antitumor activity are used as cytostatic agents included in ADC. They are inapplicable in clinical practice as self-sustained drugs due to their considerable toxicity. Of great importance for the implementation of the ADC effect is the character of a linker connecting MAB with a cytostatic agent and ensuring selective intracellular release after ADC internalization. The structure, mechanisms of action, and the results of clinical trials of a number of ADC are considered here as an illustration (by way of example). The development of ADC can help introduce new effective cytostatic agents into clinical practice.

Brentuximab vedotin is the first target drug in the treatment of hodgkin lymphoma

Progress in the treatment of Hodgkin lymphoma are among the most significant achievements of oncology of our age. Nevertheless, an early relapse or refractory course of the disease account for approximately 15–20% of cases. It was this category of patients, in which the target drug brentuximab vedotin was successfully used for the first time. This is an anti-CD30 (a cell surface antigen) humanized monoclonal antibody conjugated via a protease-cleavable linker to the cytostatic agent monomethyl auristatin E, the potent tubulin inhibitor. This article describes the characteristics of CD30 antigen and a new preparation, as well as clinical data confirming its efficacy, the results of major reviews and research on the use of brentuximab vedotin in mono and combination therapy regimens at the different stages of treatment for Hodgkin lymphoma.

Carcinoma skin in association with Chronic Myeloid Leukemia; a case report

Hydroxyurea (HU) is a cytostatic agent used to treat myeloproliferative disorders including chronic myeloid leukemia (CML), the long term use of which has been seen to be associated with multiple skin disorders. The purpose of this study was to report concomitant occurrence of multiple skin carcinomas in patients on HU & consider an alternative chemotherapeutic agent for myeloproliferative disorders.Bangladesh Journal of Medical Science Vol.16(3) 2017 p.464-466

Nimustine hydrochloride: the first crystal structure determination of a 2-chloroethyl-N-nitrosourea hydrochloride derivative by X-ray powder diffraction and solid-state NMR

Nimustine hydrochloride [systematic name: 4-amino-5-({[N-(2-chloroethyl)-N-nitrosocarbamoyl]amino}methyl)-2-methylpyrimidin-1-ium chloride], C9H14ClN6O2+·Cl−, is a prodrug of CENU (chloroethylnitrosourea) and is used as a cytostatic agent in cancer therapy. Its crystal structure was determined from laboratory X-ray powder diffraction data. The protonation at an N atom of the pyrimidine ring was established by solid-state NMR spectroscopy.