Arsenic Trioxide (ATO) Chemotherapy

A few ATO advances you should know about

Chinese scientist working in lab
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Arsenic trioxide—also known as ATO, or trisenox—is an anticancer treatment for a subtype of acute myeloid leukemia known as acute promyelocytic leukemia, or APL. This leukemia subtype is also called “the M3 subtype” of acute myeloid leukemia.

Results using ATO in the treatment of newly diagnosed patients with low-to-intermediate risk APL have been very favorable. These successes have also spurred scientific research investigating the potential use of ATO in many cancers other than APL, including non-leukemia malignancies such as metastatic colon cancer and the brain tumor, glioblastoma multiforme.

ATO is often combined with all-trans retinoic acid (ATRA), a retinoid agent used in the treatment of acute promyelocytic leukemia. Retinoid compounds can bind receptors on cells to have important actions on cellular life cycles. The combination of ATRA plus ATO has been shown to be superior to ATRA plus chemotherapy in the treatment of standard-risk patients with newly diagnosed acute promyelocytic leukemia (APL).

How Does ATO Work?

The mechanism of action of ATO is not completely understood.

In laboratory studies of human promyelocytic leukemia cells, ATO caused changes in the appearance of the cells as well as breaks in the DNA—both of which are indicative of a process known as apoptosis, or programmed cell death.

ATO also causes damage to the fusion protein made by these promyelocytic cells, called Pro-Myelocytic Leukemia/Retinoic Acid Receptor-alpha (PML/RAR alpha). Fusion proteins are proteins created through the joining of two or more genes that originally coded for separate proteins.

ATO for APL

ATO is approved for use in the treatment of certain cases of acute promyelocytic leukemia, or APL, as follows:

  • Newly diagnosed low-to-intermediate risk APL, whereby the ATO is used in combination with all-trans-retinoic acid, or ATRA.
  • Relapsed/refractory APL, in people whose previous treatments included a retinoid and chemotherapy, in the presence of certain genetic changes in the cancer cells—the t(15;17) translocation and/or the presence of pro-myelocytic leukemia/retinoic-acid-receptor-alpha (PML/RAR-alpha) gene.

A person’s white blood cell (WBC) count at presentation, or at the time of the initial evaluation and diagnosis of APL, is often used to create these APL risk groups, whereby the following categories are used:

  • Low- or intermediate-risk APL = Initial WBC count ≤10,000/microL;
  • High-risk APL = Initial WBC count >10,000/microL.

The safety and efficacy of ATO in children aged up to 17 years have not been established. No data are available for children under 5 years of age, and data are limited in older children: in one analysis, seven patients under 18 years of age (range 5 to 16 years) were treated with ATO at the recommended dose of 0.15 mg/kg/day, and five patients achieved a complete response.

The response rates of other AML subtypes to ATO have not been examined. Studies with ATO are ongoing, and in the future, there may be various additional applications for this agent in the treatment of cancer.

ATO + ATRA as Induction Therapy

The treatment of APL differs from that of other types of AML. The first step of treatment, known as induction, aims to bring about remission and involves forcing the abnormal cells of APL, the promyelocytes, to grow up into more normal cells.

All-trans-retinoic acid, or ATRA, is a non-chemotherapy drug that is often used for induction, as it forces the malignant promyelocytes to mature into neutrophils. It is a compound that is related to vitamin A. ATRA, alone, however, is generally not sufficient to do the job of inducing remission—that is, remissions with ATRA, alone, tend to be short-lived, lasting only a few months.

Thus, ATRA is usually combined with other agents to induce remission in people with APL. ATRA combined with anthracycline-based chemotherapy is the standard treatment for which there is the most extensive clinical experience and the largest amount of data.

There is quite a bit of interest, however, in the use of ATO (where available) with ATRA, in the place of standard anthracycline-based chemo. Initially, this was seen as an option for people who could not tolerate anthracycline-based chemotherapy. Recent clinical trial data, however, suggest that the combination of ATRA + ATO may produce outcomes that are just as good, if not superior to, standard regimens combining ATRA with chemotherapy—in the right patient types.

Most of the ATRA + ATO data come from studies in which people had low-risk APL and intermediate-risk APL; there is less information available about how ATRA + ATO might compare to ATRA + chemo in patients with high-risk APL.

Consolidation Therapies

As with other types of AML, patients with APL go on to receive additional treatment, well after their initial induction regimen has been completed, and this later treatment is known as consolidation therapy.

The specific drug regimens used depend in part upon what treatments were given as induction therapy. Examples of consolidation therapies follow:

  • Anthracycline + ATRA for a few cycles (different anthracyclines may be used in different cycles)
  • Anthracycline + cytarabine for at least 2 cycles
  • ATO for 2 cycles over about 75 days, then ATRA + anthracycline for 2 cycles
  • ATRA plus ATO for several cycles

Maintenance Therapies

For some patients with APL, consolidation may be followed by maintenance therapy with ATRA for at least a year. Sometimes low doses of the chemo drugs 6-mercaptopurine (6-MP) and methotrexate are given as well.

ATO for Other Disease Sites—Preliminary Research

Successes with ATO in the treatment of APL have spurred scientific interest in potential roles for ATO in the treatment of other malignancies.

In many cases, the research is very preliminary, sometimes limited to “test tubes and animal studies,” however, the fact that ATO is being explored in such a variety of different disease sites and settings is, in itself, remarkable.

A sample of these different research directions follows.

Lung Metastases from Colon Cancer

Adoptive T-cell therapy is a treatment used to help the immune system fight cancer and other diseases. T cells are collected from the patient and grown in the laboratory to maximize the odds of a successful immune system response, and then put back into the patient to fight cancer.

In an animal study by Wang and colleagues published in Oncotarget, ATO combined with cytotoxic T cells had a synergistic effect and prolonged survival time in a lung metastasis model of colon cancer. Wang and researchers noted that successes with adoptive T-cell therapy are often attributed to the reduction of regulatory T cells and that ATO may have positive effects by depleting these cells.

Lung Metastases from Liver Cancer

Given the success of ATO in APL, researchers wondered whether ATO might have a similar effect in liver cancer. Infusions of ATO have been shown to inhibit the tumor growth in liver cancer, according to a report by Lu and colleagues.

Additionally, ATO is reported to be an effective medicine in the treatment of lung metastases from liver cancer with related cancer pain. Lu and colleagues noted that studies have shown that ATO can inhibit the invasion and metastasis of liver cancer cells by inhibiting a protein called RhoC and that RhoC and its “cousin-molecule,” ezrin, may be involved in the anti-tumor function of ATO.

Therefore, they aimed to study the mechanism of the inhibition of metastatic liver cancer cells by ATO. They used the expression patterns of ezrin before and after ATO treatment as their window of observation, and they found that ATO treatment can significantly downregulate the expression of ezrin in liver cancer.

Glioblastoma multiforme

Glioblastoma multiforme, or GBM, is a fast-growing, aggressive brain tumor. This is the type of cancer that took Ted Kennedy’s life and the one that Senator John McCain was diagnosed within 2017.

Arsenic trioxide has been reported to inhibit but not regress the growth of a wide variety of solid tumors including GBM at a clinically safe dose (1–2 μM). Yoshimura and colleagues noted that a low concentration (2 μM) of arsenic trioxide could induce differentiation of GBM cells and may also enhance the effect of other anticancer therapies when used in combination in their mouse study, and the hope is that this may represent new opportunities for future GBM therapies.

Osteosarcoma

Osteosarcoma is a common bone cancer, and cure rates have not moved much in the past 25 to 30 years.

A process called autophagy refers to your cells’ lysosomes degrading and eliminating protein aggregates and damaged organelles—essentially, taking out the trash, to keep the cell’s cytoplasm clean.

Autophagy modulation has been considered a potential therapeutic strategy for osteosarcoma, and the the previous study indicated that ATO exhibits significant anti-carcinogenic activity.

Wu and colleagues recently showed that ATO increased autophagy activity in experimental human osteosarcoma cells (cell line MG-63). Interestingly, the blocking of autophagy (using drugs or genetic engineering) decreased the ATO-induced cell death, suggesting that ATO triggers autophagic cell death in MG-63 cells.

Wu and colleagues concluded, “Taken together, these data demonstrate that ATO induces osteosarcoma cell death via inducing excessive autophagy, which is mediated through the ROS-TFEB pathway. The present study provides a new anti-tumor mechanism of ATO treatment in osteosarcoma.”

A Word From Verywell

Over the last thirty years, APL has gone from a highly fatal disease to a highly curable one. Treatment strategies with ATRA, chemotherapy, and, more recently, ATO, are considered instrumental in these advances.

With these advances, there is still some “unsettled territory,” however. Longer long-term safety and efficacy of ATO can be considered here, although long-term data with ATO + ATRA reported thus far have been favorable. Another unsettled area might be which are the preferred maintenance therapies in the era of ATRA/ATO.

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Article Sources
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  • Lu W, Yang C. Effects of arsenic trioxide on the expression of ezrin in hepatocellular carcinoma. Medicine (Baltimore). 2017 Sep; 96(35): e7602.
  • Wang H, Liu Y, Wang X, et al. Randomized clinical control study of locoregional therapy combined with arsenic trioxide for the treatment of hepatocellular carcinoma. Cancer. 2015;121(17):2917-25.
  • Wang L, Liang W, Peng N, et al. The synergistic antitumor effect of arsenic trioxide combined with cytotoxic T cells in pulmonary metastasis model of colon cancer. Oncotarget. 2017;8(65):109609-109618.