Objective To review preclinical and clinical data for oxaliplatin in the current context of molecularly targeted therapy. Methods of Study Selection We searched the PubMed and PubChem databases by combining the search terms "oxaliplatin" or "platinum" or both, with "clinical trials," "pharmacokinetics," and "pharmacodynamics." Data Extraction and Synthesis Oxaliplatin has a complicated pharmacokinetic profile, with activity against digestive cancers in particular. It has several mechanisms of action, but cancer cells can develop resistance. Real or potential synergism has been observed when oxaliplatin is combined with other cytotoxic agents or molecularly targeted agents. Peripheral neuropathy is a prominent toxic effect. Conclusions Oxaliplatin lends itself to further clinical research in combination with molecularly targeted therapy.

https://www.mdpi.com/1718-7729/18/1/708/pdf

Oxaliplatin: a review in the era of molecularly targeted therapy

The immune system deploys a multitude of innate and adaptive mechanisms not only to ward off pathogens but also to prevent malignant transformation ("immune surveillance"). Hence, a clinically apparent tumor already reflects selection for those malignant cell clones capable of evading immune recognition ("immune evasion"). Metal drugs, besides their well-investigated cytotoxic anticancer effects, massively interact with the cancer-immune interface and can reverse important aspects of immune evasion. This topic has recently gained intense attention based on combination approaches with anticancer immunotherapy (e.g., immune checkpoint inhibitors), a strategy recently delivering first exciting results in clinical settings. This review summarizes the promising but still extremely fragmentary knowledge on the interplay of metal drugs with the fidelity of anticancer immune responses but also their role in adverse effects. It highlights that, at least in some cases, metal drugs can induce long-lasting anticancer immune responses. Important steps in this process comprise altered visibility and susceptibility of cancer cells toward innate and adaptive immunity, as well as direct impacts on immune cell populations and the tumor microenvironment. On the basis of the gathered information, we suggest initiating joint multidisciplinary programs to implement comprehensive immune analyses into strategies to develop novel and smart anticancer metal compounds.

Metal Drugs and the Anticancer Immune Response.

Platinum-based chemotherapy agents initially transformed cancer treatment. However their effectiveness peaked as combined regimes showed little additional benefit in trials. New research frontiers developed with the discovery that conventional chemotherapy can induce immunological cell death by recruiting high mobility group box 1 protein through T-cell immunity. Simultaneously monoclonal antibody agents (not effective as monotherapies) showed good results in combination with conventional chemotherapy. Some of these combinations are currently in use and researchers hope to develop regimes which can offer substantial benefits. Several resistance mechanisms against platinum compounds are known, but more knowledge is still needed to gain a full understanding. It seems reasonable therefore to revisit the pharmacology of these agents, which may also lead to identify rational combinations with monoclonal agents providing regimes with less toxicity and better efficacy. This article reviews the pharmacology of cisplatin and oxaliplatin and explores their possible association with monoclonal antibody treatments.

https://www.oncologyreviews.org/site/article/download/256/204

Review of Cisplatin and Oxaliplatin in Current Immunogenic and Monoclonal Antibody Treatments

Platinum-based chemotherapy made a paradigm shift in the treatment of different cancers initially; however, the success of these agents may have reached the peak as researchers have tried different combination regimes in different trials without having major differences in the end results. New frontiers of research were opened up firstly with this discovery that conventional chemo-radiation therapy can induce immunological cell death by recruiting high-mobility group box 1 (HMGB1) protein which triggers the T cell immunity and secondly monoclonal antibodies agents which were regrettably not effective as "monotherapy"; however, the combination with conventional chemotherapy had demonstrated good results. Different monoclonal antibodies and conventional chemotherapeutic combination regimes are currently in use and researchers are trying different other combinations as well to glean the maximum benefits from them. Several strategies conferring resistance to platinum compounds have been identified, but there is still significant research required to achieve full understanding of these resistance mechanisms to overcome the ineffectiveness or toxicities of platinum compounds. It seems reasonable in the current perspective when conventional chemotherapeutic agents exhibited immunogenic cell death and they are currently in use with monoclonal antibodies to revisit the platinum agent's pharmacology. This may discover new basis for combination chemotherapy with monoclonal antibodies which may improve the current cancer treatments by opening new vistas for newer combination regimes with less toxicity and better efficacy. In this article we review the pharmacologies of both cisplatin and oxaliplatin in the drug development perspectives and explore the possible association of these drugs with monoclonal antibodies.

/pdf/review-of-cisplatin-and-oxaliplatin-in-current-immunogenic-5g1yyxtfyo.pdf

Review of Cisplatin and Oxaliplatin in Current Immunogenic and Monoclonal Antibodies Perspective

Oxaliplatin is a platinum-based anticancer drug that has been shown to be genotoxic to the normal cells. Vitamin E is a potent antioxidant that may protect and enhance the repair of the damaged DNA. In this study, we aimed to evaluate the genotoxic effect of oxaliplatin on DNA by measuring the frequency of chromosomal aberrations (CAs) and sister chromatid exchanges (SCEs) in cultured human lymphocytes. We also attempted to explore the potential protective effect of vitamin E on chromosomal damage induced by oxaliplatin. Results showed that oxaliplatin significantly increased the frequency of CAs (p < 0.001) and SCEs (p < 0.001) as compared to control. This chromosomal damage, caused by oxaliplatin, was significantly decreased by pretreatment of cells with vitamin E. Moreover, the results showed that oxaliplatin caused a significant reduction in the cell kinetic parameters, the mitotic index (MI) and the proliferative index (PI). However, vitamin E did not affect this reduction in the MI and PI. T...

Vitamin E protects human lymphocytes from genotoxicity induced by oxaliplatin.

A 56-year-old woman diagnosed with a poorly differentiated cecal adenocarcinoma with metastases to ovaries, omentum, and sigmoid colon went into remission after 12 cycles of infusional 5-fluorouracil, luecovorin, and oxaliplatin (FOLFOX-4 regimen). Thirteen months later, a pelvic recurrence was diagnosed, and the patient received nine cycles of FOLFOX-6 plus bevacizumab, resulting in a clinical complete response but the development of pancytopenia. Bone marrow biopsy was consistent with therapy-related acute myelogenous leukemia. Chromosome analysis showed structural rearrangements with partial deletions of the long arms of chromosomes 5, 7, 20, and 21, as well as trisomy of chromosome 8 and losses of chromosomes 3 and 11. Induction chemotherapy led to remission, but the patient died two months later from complications of colon cancer progression. It is likely that the leukemia was related to the oxaliplatin administration.

https://theoncologist.onlinelibrary.wiley.com/doi/pdf/10.1634/theoncologist.11-3-261

Chandrika Sreekantaiah

Papers

Oxaliplatin-related acute myelogenous leukemia