Drug repurposing, also known as drug repositioning or ‘therapeutic switching,’ refers to the use of an existing drug in a novel therapeutic indication. With the increasing costs and complexity of ‘traditional’ drug discovery, this approach has become an attractive option in the development of new treatment options for hard to treat cancers. And identifying a new use for an existing, off patent authorized medicines in an indication outside the scope of the original approved indication, has become a new way to accelerate the discovery of new therapeutic options. [1][2]

Repurposing or repositioning existing drugs that may have unanticipated effects as potential candidates is just one way to help to meet the unmet medical need of patients diagnosed with a form of cancer. And while this process generally applies to pharmaceutical drugs repositioned from one therapeutic area to another, in some instances chemical compounds, used in nonbiological applications, have become powerful anticancer drugs.

Among the benefits of this approach is that these ‘old’ drugs generally involve de-risked compounds, delimiting a potential biosafety risk. This may, overall, result in lower overall development costs and shorter development timelines, and help meet the unmet medical needs of patients to access useful and novel treatments. [1][2][3]

However, while finding new therapeutic uses for existing drugs is considered desirable among policymakers, obtaining regulatory approval for new indications for existing drugs, remains costly. A results of a study, conducted between 1997 and 2020, suggest that for two-thirds of newly approved drugs, drug manufacturers did not add new indications during the post-approval period. The authors of the study concluded that this suggests that even after an off-label use comes common, nobody invests in ongoing research to secure FDA approval for the additional indication.

However, the story of repurposing old drugs and find new indications beyond the originally registered application, remains interesting. But the process is also riddled with unexpected complexities, serendipity, happy accidents and pure luck, collaboration, that when coupled with intelligence and insight to interpret the results and a creative, ‘out of the box’ thinking, may surprisingly lead to an “Eureka!” moment and the discovery of something new nobody was  looking for.

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This article reviews just some of these unexpected and serendipitous developments.

In 1960, the US Food and drug Administration (FDA) received a new drug application for a sedative, thalidomide, used for years in other countries to treat a variety of maladies, including morning sickness. FDA medical officer Frances Oldham Kelsey refused to approve the application for lack of sufficient evidence of safety. The drug was soon linked to severe birth defects in thousands of babies. The narrowly averted crisis helped usher in the 1962 Drug Amendments, requiring proof of effectiveness of drugs as well as their safety before marketing.

Thalidomide: Reversal of Fortune
The history of thalidomide shows a dark past and without a doubt it is one of the most notorious drugs of all time. When the German pharmaceutical company Chemie Grünenthal launched the drug on October 1, 1957 it was promoted to act as a tranquilizer and painkiller.

The drugs, marketed in different countries under different trade names (Contergan® and Contergan Forte® in Germany, Softenon® in the Netherlands, Kevadon® in the USA, Distaval® in the United Kingdom, etc) was originally approved and indicated as drug for the treatment of insomnia, coughs, colds and headaches. Doctors also found that thalidomide was an effective antiemetic which had an inhibitory effect on morning sickness. As a result, thousands of pregnant women took the drug to relieve their symptoms.

Despite the fact the drug had never been tested on pregnant mammals and was chemically similar to drugs known to harm embryos, the launch of the drug was supported by aggressive marketing campaigns.

In the early 1960s thalidomide, available in more than 60 countries and territories, was withdrawn because of links with severe skeletal birth defects in children born to mothers who had taken the drug in the first trimester of their pregnancies. However, around the same time potential benefit of thalidomide surfaced. Jacob Sheskin, MD, a Professor at the Hebrew University of Jerusalem at Hadassah University Hospital and the chief staff and manager of Hansen Leper Hospital in Jerusalem, noted that the drug offered treatment related benefits to patients with erythema nodosum leprosum or ENL, a painful complication of leprosy.

These developments resulted in a reversal of fortunes for the banned drug.

In the early 1960 scientists also hypothesized the drug could beneficial have anti-cancer properties. The discovery of potent anti-angiogenic properties in the 1990s renewed interest in the use of thalidomide as an antitumor agent. Following extensive clinical research, thalidomide was first approved in 2006 by the FDA for use in combination with dexamethasone in patients with newly diagnosed multiple myeloma. It was also authorized in the EU in 2008, in combination with melphalan and prednisone, and is indicated as first-line treatment of patients with untreated multiple myeloma who are aged 65 years and over or ineligible for high-dose chemotherapy. [4]

Bottle with aspirin, 1899 (Source: Archives of Bayer AG, Llicence Creative Commons Attribution 3.0).

A miracle drug: acetylsalicylic acid
Acetylsalicylic acid (Aspirin®; Bayer) was originally developed at the end of the 19th century and marketed for the treatment of inflammatory disorders and used as an analgesic.While its mechanism of action remained unknown until the second half of the 20th century, observational evidence indicating a reduction in the risk of colorectal cancer after prolonged use started to emerge in the late 1980s. Data from both experimental and observational studies have demonstrated that aspirin may play a role in preventing different types of cancer. [5]

In 2016, following a number of studies, the U.S. Preventive Services Task Force released a Final Recommendation Statement on initiating low-dose aspirin use for the primary prevention of cardiovascular disease and colorectal cancer in adults aged 50–59 years who have a 10% or greater 10-year cardiovascular disease risk, are not at increased risk for bleeding, have a life expectancy of at least 10 years and are willing to take low-dose aspirin daily for at least 10 years

However, in contrast to prior randomized controlled trials involving younger individuals, demonstrating a delayed cancer benefit with aspirin, a randomized, double-blind, placebo-controlled trial of daily low-dose aspirin (100 mg) in older adults, in Australia showed an increase in all-cause mortality, primarily due to cancer. [6][7][8]

The Story of Disulfiram
Among the evaluation of ‘old’ drugs for a new use in oncology is disulfiram (Antabuse®; Duramed Pharmaceuticals/Physicians Total care/Sigmapharm Laboratories).

The early history of disulfiram, also known as known tetraethylthiuram disulfide, goes back to 1881. In that year, M. Grodzki, a chemist in Berlin, Germany, reported that he had synthesized a new compound from thiocarbamide with a  stoichiometric formula of C10H20N2S4. Grodzki’s report discussing the new substance, published in Berichte, did not receive much attention, until the early 1920s when it was introduced as a substance which proved effective in accelerating the vulcanization of both natural rubber and synthetic rubber products. [9][10]

It was an incidental observation by E. E. Williams, MD, a physician working for the United States Rubber Company (now part of Michelin Group), that would change the future of what would result in disulfiram becoming a drug. Williams reported that workers in the company’s factory who were exposed to disulfiram experienced unpleasant hypersensitivity and related symptoms after consuming alcohol. However, while he considered that, as a result of the adverse properties of disulfiram to alcohol, it could possibly lead to a potential “cure for alcoholism,” Williams did not follow up on this suggestion and, in the end, nothing came of it. [11]

In the early 1942 two physicians in Britain observed that disulfiram could kill scabies, leading to the compound as a promising scabiescide.[12] At the same time, Swedish scientists studying the effect of the disulfide in killing intestinal worms and noted that the compound appeared to interrupt the actions of copper-containing enzymes present within mite cells, compromising their ability to generate energy, leading to the death of Sarcoptes scabiei, the scabies mite.[13][14]

These findings were noted by Jens Hald, MD, the chief of the Copenhagen-based pharmaceutical company Medicinalco, who would, in 1962, be appointed as professor of pharmacology at the Pharmaceutical College (now part of the University of Copenhagen) and Erik Jacobsen, Ph.D., a pharmacologist and experienced analytical chemist at Medicinalco.  The two Danish researchers soon realized that the science behind the scabiescide effect of disulfiram was due to its ability to absorb copper and form chelates with the metal. Based on their observation that the compound was an effective vermicide, they believed that the compound could also work in humans.  To confirm their hypothesis and understanding the side effects, Hald and Jacobsen tested disulfiram on themselves, accidentally confirming that when alcohol is ingested in combination with the compound, the results are unpleasant.

Their experiment did not immediately result in the development of disulfiram as an alcohol antagonist drug. An accidental meeting between Jacobsen and Oluf Martensen-Larsen, MD, a physician who had experience with treatment of alcoholics, ultimately resulted in recognizing that disulfiram could possibly be used as a drug for the treatment of alcohol dependancy.[15][16]

The resulted on clinical trials to better understand the physiological actions of the drug and to establish its safety, tolerability and efficiency, which, in turn led several years later to the drug called Antabuse, which was originally approved by the US Food and Drug Administration (FDA) a in 1951 as an alcohol antagonist drug.

In the years since the drug registration, research in other therapeutic uses have continued, including symptoms caused by vitamin E deficiency [17][18], the treatment of cocaine-dependence [19] and co-occurring cocaine and ethanol addiction, possibly through inhibiting dopamine β-hydroxylase (DβH), and as a promising drug in the treatment of addictions associated with other widely used psychoactive and/or depressive substances. [20][21]

In a number of studies disulfiram has shown to be safe and have the potential to target different forms of cancer, including non-small cell lung cancer (NSCLC), liver cancer, (metastatic) breast cancer, prostate cancer, colorectal cancer, pancreatic cancer, glioblastoma (GBM) and melanoma.[22][24]

Researchers believe that disulfiram inhibits NFkB signalling, proteasome activity, and aldehyde dehydrogenase (ALDH) activity. It induces endoplasmic reticulum (ER) stress and autophagy and has been used as an adjuvant therapy with irradiation or chemotherapy drugs. Disulfiram has also shown to target cancer stem cells, which provides a new approach to prevent tumour recurrence and metastasis. Research has also shown that disulfiram binds to nuclear protein localization protein 4 (NPL4) and induces its immobilization and dysfunction, ultimately leading to cell death. [22] In combination with copper, disulfiram induced reactive oxygen species (ROS) generation and activated its downstream apoptosis-related cJun N-terminal kinase and p38 MAPK pathways.[23]. Other research demonstrated that disulfiram, asa DNA methyltransferase inhibitor, may provide benefit for patients with prostate cancer by restoration of tumor suppressor genes and that disulfiram or its metabolites permanently inactivate the human multidrug resistance P-glycoprotein or reverses either MDR1- or MRP1-mediated drug efflux.

However, research has shown that the use of disulfiram may be limited by its (very) short half-life in the bloodstream. This has prompted the development of a (PEGylated) liposome-encapsulated formulation disulfiram, which, in preclinical studies, showed to block NFκB activation and specifically targeted cancer stem cells (CSC) in vitro. The results also demonstrated that the liposomal formulation targeted cancer stem cells in vivo and showed very strong anticancer efficacy, was well tolerated (in mice) without significant in vivo nonspecific toxicity. [24][25]

Beyond cancer
Research in the anticancer applications of disulfiram is ongoing. In addition, the drug is being studies in other therapeutic areas. In an article published in the August 2020 journal Cell Metabolism, researchers describe the results of a a study in which disulfiram treatment prevented body weight gain in mice fed a high-fat diet. The same study demonstrated beneficial effects of disulfiram as a treatment to lower body weight in diet-induced obese mice. Their data suggesting that it might be possible to repurpose or reposition disulfiram to treat people with obesity and in 2021 a Alejandro E. Macias, MD, MS, a Clinical Microbiologists, and his colleagues at Universidad de Guanajuato, Mexico, started an early phase 1 study designed to test further establishment of guidelines for clinical studies focused the use of disulfiram as an adjunct in the reduction and control of body weight.

Dexrazoxane,a bisdioxopiperazine known as ICRF-187 is clinically used as a doxorubicin cardioprotective agent and may act by preventing iron-based oxygen free radical damage through the iron-chelating ability of its fully hydrolyzed metabolite ADR-925; chemically (N,N’-[(1S)-1-methyl-1,2-ethanediyl]-bis[(N-(2-amino-2-oxoethyl)]glycine).
Another examples: Dexrazoxane
Dexrazoxane b, a bisdioxopiperazine known as ICRF-187/ADR-529, is an intracellular iron chelator which decreases the formation of superoxide radicals indicated for the use as a cardioprotective agent in anthracycline-induced cardiotoxicity and prevention of tissue injuries after extravasation of anthracyclines. [26]

Nonbiological properties
However, in the 1950s and early 1960s, bisdioxopiperazine compounds were independently investigated by scientists at Eastman Kodak and Ciba-Geigy , for nonbiological and non-pharmaceutical properties including the use as jet fuel additivestextile leveling or setting agents, pharmaceutical intermediates, textile auxiliaries, and curing agents.

In the early 1960s, the use of bisdioxopiperazine derivates as medicinal agents was unknown and the anticancer activities of these compounds was unanticipated and unexpected.

Then, in the late 1960s, with a better understanding of the chemistry of bisdioxopiperazine derivates, scientists, including Eugene H. Herman, MD, Ph.D, at the Toxicology and Pharmacology Branch of the National Cancer Institute, discerned that dexrazoxane is hydrolyzed intracellularly to form a bidentate chelator, similar in structure to ethylenediaminetetracetic acid (EDTA), and quickly binds intracellular iron.nHowever, unlike EDTA, dexrazoxane easily passes into cells, where, upon hydrolysis, it opens into its EDTA-like form, known as ADR-925, which is a strong iron chelator that has the ability to displace iron from anthracyclines.

Based on this observation, scientists started to formulate a hypothesis that suggested that the intercellular metal ion chelation leads to retardation of neoplastic cell growth.

In early 1967, based on the potential applications as a pharmaceutical compound, the National Research Development Corporation (NRDC), a non-departmental government body established by the British Government to transfer technology from the public sector to the private sector, obtained a patent for bisdioxopiperazine compounds.  [27]

In turn Imperial Cancer Research Technology d synthesed  a number of potential bisdioxopiperazine compounds (registering them under the name of the sponsoring organization, Imperial Cancer Research Fund (ICRF) erazoxane as ICRF-159, dexrazoxan as ICRF-187, ICRF-193 and ICRF-154). f  [28]

Based on observed in vitro antineoplastic effects in various tumors as well as in vivo activity shown in 6 patients with acute leukemia and lymphosarcoma who received ICRF-159, the the racemic form of dexrazoxane, K. Hellmann, DM, D.Phill, head of the Chemotherapy Department at the at the Imperial Cancer Research Fund and his colleagues suggested that these chelating compounds might be antineoplastics “worth further examination in all forms of acute leukemia and lymphosarcoma.” [29][30][31][32][33]

But medical scientists soon realized that bisdioxopiperazine derivates were neither cytotoxic nor selective for tumor cells. Furthermore, they found that while these agents were cytostatic, they inhibiting cell growth at only one brief period in the cell cycle progression (late in G2/M), without any inhibitory effects at any other phase in the cell cycle. They also observed that razoxane and dexrazoxane were nonselective.  They affected both normal, health, cells and malignant, tumors, cells equally.

And while razoxane/ICRF-159 and dexrazoxane/ICRF-187 were, in the 1970s, investigated for anti-tumor activity, in acute leukemia, lymphosarcoma, non-Hodkins and breast cancer, both compounds were found to have little effect against human tumors when administered as single agent.  Furthermore, In the 1980s, reports of secondary toxicities during treatment of psoriasis prevented razoxane from entering Phase III clinical trials for its use as a standalone anticancer agent.

It is a cardioprotector…
The potential of bisdioxopiperazines as protectors against anthracycline-mediated myocardial damage emerged from multiple preclinical studies.  One of these studies, published in 1974 by Herman et al., demonstrated that anthracycline-induced cardiotoxicity was prevented in isolated dog hearts that were pretreated with perfusions of razoxane. [34]

Not much later, in a series of classical papers, Herman and Ferrans, in collaboration with researchers at the NIH and FDA reported that pretreatment with dexrazoxane/ICRF-187 reduced cardiotoxicity and lethality in non-cancer-bearing Syrian golden hamsters receiving daunorubicin. In a series of additional studies, the researchers further demonstrated that pretreatment with dexrazoxane was shown to be cardioprotective in doxorubicin- and daunorubicin-treated beagle dogs, rabbits, and miniature swine.

These studies demonstrated that animals treated with ICRF-187 had prolonged survival and did not develop the pathological cardiac lesions commonly associated with anthracycline toxicity, while protection was afforded at doses that were not toxic to the animals, and did not have a negative effect on other, non-cardiac, toxicities, including alopecia and myelosuppresssion. [35][36][37][38]

In a meeting held in October 1991 in Pisa, Italy, Herman, Ferrans, Speyer and representatives from Industry, including Cetus/EuroCetus (now part of Novartis), the National Institutes of Health, the National Heart, Lung and Blood InstituteThe Netherlands Cancer Institute collectively discussed the clinical implications of ICRF-187 as a cardioprotective agent, and potential future development the investigational agent.

Later, in clinical studies, James L. Speyer, MD, at Department of Medicine at Rita & Stanley Kaplan Cancer Center, New York (now part of NYU Langone Medical Center), confirmed that dexrazoxane excepted cardioprotection in humans. g [39]

The mechanism of action in which dexrazoxane/ICRF-187 offers cardioprotection is that it strips Fe2+ from the iron-doxorubicin complex, thereby preventing free radical generation that damages cells. Dexrazoxane reduces doxorubicin-induced cardiac damage as measured by clinical examination, multigated nuclear medicine (MUGA) scans, or endornyocardial biopsy. [40] As a result, coadministration of dexrazoxane with an anthracycline has been shown to improve survival and to minimize functional change of the heart.

… a topoisomerase II inhibitor
At the same time, dexrazoxane is also a catalytic inhibitor of DNA topoisomerase II, which is also the same target as the DNA topoisomerase II cytotoxic anticancer agents, including anthracyclines (i.e doxorubicin, epirubicin, daunorubicin), the anthracenediones (eg, mitoxantrone), and the podophyllotoxins (eg, etoposide, teniposide). [41]

Dexrazoxane works by locking topoisomerase II at a point in the enzyme reaction cycle where the enzyme forms a closed clamp around DNA. This mechanism of action is considered to be the main reason for its cytotoxicity against quickly proliferating cancer cells. However, as a catalytic noncleavable complex-forming inhibitors of DNA topoisomerase II, dexrazoxane, in contrast to cytotoxic anticancer agents, does not induce lethal protein-linked DNA double strand breaks. [42]

In recent developments, one study suggests that dexrazoxane may act as a beneficial neuroprotectant to treat neurodegeneration in patients with Parkinson’s disease. [43] Unrelated to this development, scientists believe that dexrazoxane could be used as a prodrug to synthesize new antimalarial agents. [44]

Dexrazoxane (Cardioxane®; Chiron) was initially licensed in 1992. Subsequently, Novartis acquired the product as part of the company’s 2006 acquisition of Chiron. The product is currently marketed and distributed by the UK-based Clinigen Group and licensed for sale in 22 markets around the world, including 10 countries in Latin America.

In the United States dexrazoxane (Zinecard®; Pfizer/Pharmacia & Upjohn) was approved in 1995.

Metformin: beyond diabetes 
Another example of repurposing ‘old’ drugs is metformin, a dimethylguanide, part of the biguanide group, is widely prescribed as an anti-diabetic for the treatment of type 2 diabetes (T2DM). However, accumulating evidence suggests that it is effective for treating many cancers, including breast cancer and multiple myeloma.

Metformin is reported to inhibit cancer growth by lowering elevated levels of insulin, inhibiting oxidative phosphorylation (OXPHOS), defined as an electron transfer chain driven by substrate oxidation that is coupled to the synthesis of ATP through an electrochemical transmembrane gradient. In addition, metformin has demonstrated to inhibits the proliferation of myeloma cells by inducing autophagy and cell-cycle arrest, suggesting a molecular mechanism involving dual repression of both mTORC1 and mTORC2 pathways, essential for tumor cell growth, proliferation and survival, via the activation of adenosine monophosphate activated protein kinase (AMPK). Based on clinical observations, researchers believe that AMPK activation and/or the reduction of serum insulin levels are the main mechanisms underlying the anti-cancer activity of metformin. [45][46]

In addition, long-term use of metformin significantly reduced the risk of breast cancer in patients with type 2 diabetes.

Clinical trials to test the therapeutic potential of metformin for multiple cancers, including breast cancer, pancreatic cancer, prostate cancer, and multiple myeloma are ongoing.

Imipramine: from antidepressant to anticancer agent
In a recent development, researchers at the Mays Cancer Center at UT Health San Antonio,Tx, are putting an ‘old’ drug to new use treating breast cancers that don’t respond to existing therapies. The drug, imipramine (Tofranil-PM™; Mallinckrodt), is a tricyclic antidepressant (TCA) mainly used as an antidepressant for the treatment of major depressive disorder, but also indicated as an effective drug in the treatment of anxiety, panic disorder, and as a treatment of nocturnal enuresis (also informally called bedwetting or involuntary urination while asleep after the age at which bladder control usually begins).

The drug, first approved by the U.S. Food and Drug Administration in 1959 , showed anticancer activity in patients diagnosed with breast cancer in a pilot clinical trial conducted at the Mays Cancer Center at UT Health San Antonio.

Ratna K. Vadlamudi, Ph.D. is Professor of obstetrics and gynecology and Vice Chair for Research in the Department of Obstetrics & Gynecology at UT Health San Antonio. His current research focuses on the characterization of novel oncogenes and tumor suppressors, endocrine therapy resistance, the development of novel cancer therapeutics for breast, ovarian, endometrial, and gynecological malignancies, as well as estrogen signaling in these diseases. Photo courtesy: UT Health San Antonio. Used with permission.

Compelling evidence
Research in the Joe R. and Teresa Lozano Long School of Medicine at UT Health San Antonio provided compelling evidence of the drug’s anticancer activity. The discovery led to a clinical trial that benefited 15 breast cancer patients at the Mays Cancer Center.

Long prescribed to cancer patients to fight depression, researchers have reported anecdotally that imipramine also appears to have anticancer activity, said Ratna K. Vadlamudi, Ph.D., professor of obstetrics and gynecology and co-leader of the Cancer Development and Progression Program at the Mays Cancer Center.

New beginnings
The Vadlamudi laboratory is a training ground for tomorrow’s scientists — postdoctoral fellows, graduate students and younger scholars. Vadlamudi, who has made many research discoveries in cancer, advised his protégés that the National Cancer Institute (NCI), part of the National Institutes of Health (NIH), prioritizes the repurposing of FDA-approved drugs as cancer treatments. He showed the youngest team member, Arhan Rao, a library of approved drugs. Rao studied the list and made observations. He asked if the laboratory might set its sights on imipramine. Vadlamudi and his team agreed.

Triple-negative and Estrogen Receptor-positive
The results are exciting. Imipramine inhibits triple-negative breast cancer (TNBC) and estrogen receptor-positive breast cancer (ER+) in both mouse and human tumors. These two cancers are notoriously difficult to treat in patients.

Triple-negative breast cancer (TNBC) occurs in less than 15% % of cases of breast cancer but is the most aggressive subtype and has the worst prognosis because it does not express the hormone receptors estrogen receptors (ER) and progesterone receptors (PR) and the human epidermal growth factor receptor 2 (HER2).

The study results, reported in the August 1, 2022 issue of Cancer Letters, [48] demonstrated that showed that imipramine blocks ER+ and TNBC growth and progression by inhibiting key proteins involved in ER-α signaling, cell cycle progression, and DNA repair and replication. The results also indicated that imipramine improved the efficacy of PARP inhibitor therapy in TNBC and anti-estrogen in ER + breast cancer. b

Virginia Kaklamani, MD is professor of medicine in the Division of Hematology and Medical Oncology at the University of Texas Health Sciences Center San Antonio and is the leader of the breast cancer program at the Mays Cancer Center, home to UT Health San Antonio MD Anderson.

This solid foundation of knowledge set the table for the clinical trial directed by Virginia Kaklamani, MD, leader of the Breast Cancer Program at the Mays Cancer Center and professor of medicine in the Long School of Medicine. The clinical team gave imipramine to women newly diagnosed with breast cancer who awaited surgery.

“We typically have a window of two to three weeks or so between the diagnosis and the surgery, and this is an opportunity for us to give patients a drug and test to see how it does on cancer tissue,” Kaklamani said.

The care team obtains a biopsy as part of the initial diagnosis and another tissue specimen during surgery. “This affords two time points so we can see how the cancer has changed with the imipramine treatment,” Kaklamani said. “We did that in 15 patients, and overall, we were able to show that imipramine can decrease tumor growth.”

This small pilot study, funded by the Mays Cancer Center, is a preliminary experiment to show that imipramine is an active drug in breast cancer, Kaklamani said.

“FDA-approved drugs will be safe, as they are used to treat other diseases,” Vadlamudi said. “If the same drugs work to kill cancer cells, then they can be used in clinics right away.”

The developments and examples describes in this overview perfectly reflect the National Cancer Institute’s goal to repurpose existing drug therapies for cancer, and it gives new hope to cancer patients worldwide who are diagnosed with these hardest-to-treat breast cancers.

But to really succeed in “repurposing” or “repositioning” old and existing drugs, it is important to have an open mind, think outside the box and be prepared, and to remember what Louis Pasteur once said: “Dans les champs de l’observation, le hasard ne favoriseque les esprits prepares” (In the field of observation, chance favors only the prepared mind).

a Disulfiram was approved in Denmark and Sweden in early 1949.

b Dexrazoxane, (+/-)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane (ICRF-187), is indicated for prevention of chronic cumulative cardiotoxicity caused by doxorubicin or epirubicin in the treatment of patients with advanced and/or metastatic  breast cancer who have received a prior cumulative dose of 300 mg/m2 of doxorubicin or 540 mg/m2 of epirubicin and when further anthracycline treatment is required. The recommended dose ratio (dexrazoxane:doxorubicin or dexrazoxane:epirubicin) is 10:1. In this setting, dexrazoxane is administered as an intravenous infusion 10–30 minutes before the anthracycline. For this indication, the drug is marketed as Zinecard® (USA) and Cardioxane® (Clinigen Healthcare; Europe). Dexrazoxane is also indicated for the prevention of tissue injuries from extravasation of anthracyclines. In this indication, the recommended schedule is 1,000 mg/m2 intravenously within 6 hours after the extravasation incident, followed by intravenous administration of 1,000 mg/m2 and 500 mg/m2 after 48 and 72 hours, respectively. For this indication dexrazoxane is marketed as Totect™ (Cumberland Pharmaceuticals; USA) and Savene® (Clinigen Healthcare; Europe).

c Following the merger Ciba-Geigy and Sandoz that created Novartis, non-pharmaceutical activities were spun out in 1997. The new chemical company, called Ciba was, in 2008, acquired by the German chemical company BASF and, in April 2009, integrated into the BASF group. Ciba AG initially continued to trade under the old name, but was renamed to BASF Schweiz AG in March 2010. Although this patent related to the non-pharmaceutical application of bisdioxopiperazine compounds, the current assignee of this patent (GB978724A) is Novartis.

d Imperial Cancer Research Technology is now Cancer Research UK (CRUK) Commercial Partnerships. In 2002 Cancer Research Technology (CRT) was formed by merging Cancer Research Campaign Technologies, Cancer Research Ventures and Imperial Cancer Research Technology. In 2016 Cancer Research Technology (CRT) became CRUK Commercial Partnerships

e The Imperial Cancer Research Fund (ICRF) was founded in 1902 as the Cancer Research Fund, changing its name to the Imperial Cancer Research Fund in 1904. In 2002 -following the merger of The Cancer Research Campaign and the Imperial Cancer Research Fund, Cancer Research UK (CRUK) is the world’s largest independent cancer research organization, was established

f Razoxane (ICRF-159) and the dextro enantiomer of razoxane, dexrazoxane (ICRF-187), which is more water soluble, and, as a result, is the preferred isomer for the preparation of parenteral injections.

Clinical trials
Body Weight Response With Disulfiram in Humans – NCT05162001
Vinorelbine, Cisplatin, Disulfiram and Copper in CTC_EMT Positive Refractory Metastatic Breast Cancer – NCT04265274
Imipramine on ER+ve and Triple Negative Breast Cancer – NCT03122444

Highlights of prescribing information
Imipramine pamoate (Tofranil-PM™; Mallinckrodt) [Prescription Information]
Dexrazoxane (Zinecard®; Pfizer/Pharmacia & Upjohn) [Prescribing information]
Dexrazoxane (Totect®; Cumberland Pharmaceuticals)[Prescribing Information]

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