Received: 15-Nov-2022, Manuscript No. IJDDR-22-13201 ; Editor assigned: 18-Nov-2022, Pre QC No. IJDDR-22-13201 ; Reviewed: 23-Nov-2022, QC No. IJDDR-22-13201 ; Revised: 26-Nov-2022, Manuscript No. IJDDR-22-13201 ; Published: 30-Nov-2022, DOI: 10.36648-0975-9344-14.11-981
Conventional Chemotherapy; Arsenic Trioxide
Metal compounds have been used to treat a variety of illnesses, including cancer, successfully in medicine since ancient times. Following Barnett Rosenberg's 1960 discovery of cisplatin, platinum-based medicines assumed a crucial role in systemic therapy for a variety of cancers. Present-day systemic oncological therapy regimens still rely heavily on platinum compounds, which, depending on the kind of cancer, might result in high response rates or even cures .
However, significant obstacles to the so-called "conventional chemotherapy" used to treat cancer remain, chief among them the unfavourable effects based on the cytotoxic activity also against healthy tissues and the rapid emergence of drug resistance as a result of the enormous genomic and epigenetic flexibility and adaptability of the cancer cells. Additionally, precision medicine ideas have been integrating into oncological treatment strategies, shifting conventional chemotherapies out of focus, based on the deciphering of the human genome and the accessibility of highthroughput sequencing methods.
Since non-malignant tissues could not be damaged and resistance development would be less effective, the scientific community felt that the precise explanation of oncogenic driving mechanisms would enable the treatment of patients with late stage cancer with more accuracy. Partially, and particularly in the field of haematology, these promises have been fulfilled, but in patients with solid tumors—even after initial responses—targeted drugs frequently fail because of rapid resistance development [2- 5]. Recent advancements in systemic cancer therapy based on immune checkpoint inhibitor-based cancer immunotherapy have shown astounding outcomes in tumour types with extraordinarily high mutation rates, such as melanoma, bladder cancer, and smoking-associated lung cancer.
Despite this, immune-based modern treatments only significantly benefit a small percentage of cancer patients.As a result, approaches that combine conventional and targeted therapies are currently being evaluated. This has also sparked a revival of traditional mutagenic chemotherapy strategies to increase cancer immunogenicity.In parallel, it became clear that anticancer metal drugs might be more than just cytotoxic agents that kill all proliferating cells; in fact, they might also hit specific cancer targets.The discovery of the molecular mechanism underlying the antileukaemic effect of arsenic trioxide (ATO), the oldest human-use metal remedy, was one of the most impressive proofs of that concept.The oncogenic nucleophosmin-retinoic acid receptor (NPM-RAR) alpha fusion gene product is the target of this cytotoxic compound, which results in the release of the blockade of terminal differentiation in cells of acute promyelocytic leukemia .
As a result, other clinically used metal drugs have also been examined more closely, and the results have been surprising.As a result, it has been demonstrated that, in contrast to cisplatin, oxaliplatin causes immunogenic cell death of cancer cells, resulting in a vaccination effect.This example vividly illustrates the possibility that our understanding of conventional chemotherapy is frequently oversimplified, given that DNA platination is widely believed to be the primary mode of action for both compounds.
As a result, numerous novel metal compounds have been synthesized and tested in clinical studies for their anticancer activity.Surprisingly, novel anticancer metal compounds were not recently approved for clinical use despite this enormous effort.One possible explanation is that synthetic chemists cannot precisely determine the mode of action during the design and evaluation of metal compounds, which hinders optimization strategies.The development of anticancer metal drugs has primarily focused on ruthenium compounds, in addition to platinum and gold.The redox nature of this platinum group metal, which permits ruthenium oxidation states +II and +III under physiological conditions, is primarily what makes it appealing for the development of drugs that target specific tumors.Prodrug strategies based on activation by reduction in the reductive environment of solid tumors are possible because Ru(III) is significantly less reactive than Ru(II) .
An intriguing first-in-man clinical phase I study of a Ru(III) prodrug known as IT-139 (formerly NKP-1339 or KP1339) is now available online in ESMO by Burris et al.A dual prodrug design approach has been utilized for this novel metal complex. IT-139 is systemically inactivated by effective binding to serum proteins like albumin and transferrin in the blood stream, in addition to being activated by reduction from Ru(III) to Ru(II). As a result, the compound has a moderate in vitro cytotoxicity when there is sufficient fetal calve serum, but its half-maximum inhibitory concentration drops dramatically when serum is depleted. As a result, the concept of "enhanced permeability and retention" or EPR effect allows the protein-bound drug to enter the interstitium of the tumor tissue while healthy tissues with intact blood vessels are unaffected. To satisfy the tumor's insatiable demand for anabolic building blocks, the still inactive, protein-bound prodrug is preferentially taken up by malignant cells via endocytosis.
Based on the clinical response or disease control observed in the current phase I study, absence of neutropenia, and minimal adverse effects, the tumor-targeting concept appears to work for IT-139.With a maximum tolerated dose (MTD) of 625 mg/m2, IT-139 allowed for relatively high doses and a longer treatment duration due to its low toxicity. Thus, IT-139 addresses a first-in-class ruthenium-based little particle that — other than promising action and cancer explicitness in preclinical examinations — has serious areas of strength for conveyed for a satisfactory helpful window likewise in the clinical stage I setting. In contrast, imidazoliumtrans- dimethylsulfoxide-imidazoletetrachlororuthenate, also known as NAMI-A, was the only other ruthenium compound that had been tested in a clinical phase I/II study previously. This compound only permitted the application of significantly lower doses. A single stable disease and no clinical responses were observed at the MTD of 300 mg/m2/day; Higher doses caused painful blisters to form on the hands and feet, and corticosteroids had to be taken before use to avoid hypersensitivity reactions. IT-139, on the other hand, targeted all types of lesions, including the primary tumor, while NAMI-A only had antimetastatic effects in preclinical animal models. Already, these observations point to differences in the distribution of tissues and, most likely, in the mode of action. In prior studies, DNA was thought to be the primary target of all anticancer metal drugs; however, this hypothesis has since been revised. As a result, IT-139 exhibits a distinct protein-binding pattern inside the cell, which is consistent with its uptake as a protein-conjugate and accumulation, such as in the lysosomes. It is interesting to note that the drug's affinity for ATP-binding cassette (ABC) transporter efflux pumps, including ABCB1, is also significantly reduced by this serum protein-bound uptake mechanism. IT-139, on the other hand, may not only be capable of evading drug resistance mechanisms, but its mode of action appears to also involve the inhibition of an important cellular protection mechanism.It was recently demonstrated that IT-139 inhibits stress-induced upregulation of the glucoseregulated protein of 78 kDa (also known as BIP) When GRP78 is inhibited, tumor cells become more susceptible to endogenous metabolic and radical stress, hypoxia, and the effects of cytotoxic compounds. GRP78 is a major chaperon of the unfolded protein response (UPR) that is upregulated in multiple therapy-resistant tumors. Additionally, malignant cells spontaneously exhibit elevated levels of UPR and endoplasmic reticulum (ER) stress due to increased protein damage.We recently discovered that IT-139 exposure of cancer cells in vitro affects other important chaperones, including major heat-shock proteins (manuscript in preparation), in addition to GRP78. These results suggest that IT-139, along with redox-based ROS induction, mediates tumor cell apoptosis and resistance reversion in a "two-edged sword" fashion and typically targets cellular protein repair [8-10]. This is consistent with the compound's synergistic activity with drugs that induce protein damage and ROS production in vitro.
In the Burris et al. study, IT-139 has a moderate activity, with a disease control rate of 26% and only one partial response in a colon cancer patient. However, it is important to keep in mind that the majority of patients who were included in the study had previously received multiple treatment regimens and had progressive, therapy-refractory disease.In addition, a phase I trial's primary objective is unquestionably not to demonstrate efficacy. It is interesting to note that three of the ten patients whose disease was controlled by IT-139 had neuroendocrine tumors (NET; out of the five NET patients in the study, two had carcinoids and one had gastrinoma). When they were taken out of the study, all three patients had non-progressive disease that was stable, in one case even after 98 weeks. Because NETs are frequently resistant to well-established systemic therapies like chemotherapy and targeted drugs, this tumor selectivity is intriguing. In addition, it has recently been suggested that the intrinsic ER stress levels in pancreatic NET are particularly high. As a result, it will be interesting to see if this single drug has anti-NET activity in phase II.However, in the majority of these therapy-resistant patients, it appears that IT-139 alone is insufficient to achieve significant tumor responses by blocking the stress-induced upregulation of GRP78. As a result, and as a result of the complete absence of neutropenia, IT-139 might be an excellent candidate for approaches that combine it with chemotherapeutics or targeted compounds.In preclinical in vivo models, IT-139's synergistic activity with a number of targeted and chemotherapeutic compounds has already been observed, and the evaluation in clinical studies is desirable.To summarize, anticancer metal compounds have made their way into molecularly targeted cancer therapy.
The author would like to acknowledge his Department of Pharmacogenomics, Center for Medicine, Spain, for their support during this work.
The author has no known conflicts of interested associated with this paper.
Citation: Barley J (2022) Attacking of Metal Drugs Occurs. Int J Drug Dev Res J, Vol. 14 No. 11: 981.