The anthracyclines: will we ever find a better doxorubicin?
TL;DR: Current studies are evaluating increased doses of epirubicin to improve anthracycline cytotoxicity, while limiting cardiotoxicity, but at present DOX still reigns in this drug class as the one having the most proven cancerocidal effect.
About: This article is published in Seminars in Oncology.The article was published on 1992-12-01 and is currently open access. It has received 762 citations till now. The article focuses on the topics: Anthracycline & Idarubicin.
Citations
More filters
TL;DR: An overview of issues confirms that anthracyclines remain “evergreen” drugs with broad clinical indications but have still an improvable therapeutic index.
Abstract: The clinical use of anthracyclines like doxorubicin and daunorubicin can be viewed as a sort of double-edged sword. On the one hand, anthracyclines play an undisputed key role in the treatment of many neoplastic diseases; on the other hand, chronic administration of anthracyclines induces cardiomyopathy and congestive heart failure usually refractory to common medications. Second-generation analogs like epirubicin or idarubicin exhibit improvements in their therapeutic index, but the risk of inducing cardiomyopathy is not abated. It is because of their janus behavior (activity in tumors vis-a-vis toxicity in cardiomyocytes) that anthracyclines continue to attract the interest of preclinical and clinical investigations despite their longer-than-40-year record of longevity. Here we review recent progresses that may serve as a framework for reappraising the activity and toxicity of anthracyclines on basic and clinical pharmacology grounds. We review 1) new aspects of anthracycline-induced DNA damage in cancer cells; 2) the role of iron and free radicals as causative factors of apoptosis or other forms of cardiac damage; 3) molecular mechanisms of cardiotoxic synergism between anthracyclines and other anticancer agents; 4) the pharmacologic rationale and clinical recommendations for using cardioprotectants while not interfering with tumor response; 5) the development of tumor-targeted anthracycline formulations; and 6) the designing of third-generation analogs and their assessment in preclinical or clinical settings. An overview of these issues confirms that anthracyclines remain "evergreen" drugs with broad clinical indications but have still an improvable therapeutic index.
3,320 citations
Cites background from "The anthracyclines: will we ever fi..."
...The last 2 decades have witnessed numerous attempts to identifying novel anthracyclines that proved superior to DOX or DNR in terms of activity and/or cardiac tolerability (Weiss, 1992)....
[...]
...I. Introduction 1Anthracyclines rank among the most effective anticancer drugs ever developed (Weiss, 1992)....
[...]
TL;DR: This review summarizes historical and scientific perspectives of Doxil development and lessons learned from its development and 20 years of its use and demonstrates the obligatory need for applying an understanding of the cross talk between physicochemical, nano-technological, and biological principles.
3,189 citations
TL;DR: The tumors most commonly responding to doxorubicin when it is given as a single agent or in combination with other antitumor agents include breast and esophageal carcinomas; osteosarcoma, Kaposi's sarcoma and soft-tissue sarcomas; and Hodgkin's and non-Hodgkin's lymphomas.
Abstract: Doxorubicin (Adriamycin) has been used in oncologic practice since the late 1960s. It held promise as a powerful drug in the fight against cancer. The tumors most commonly responding to doxorubicin when it is given as a single agent or in combination with other antitumor agents include breast and esophageal carcinomas; osteosarcoma, Kaposi's sarcoma, and soft-tissue sarcomas; and Hodgkin's and non-Hodgkin's lymphomas. Other cancers that are less responsive to doxorubicin but that are still treated with the drug because of its overall benefits include gastric, liver, bile-duct, pancreatic, and endometrial carcinomas. However, reports of fatal cardiotoxic effects of doxorubicin have . . .
1,687 citations
TL;DR: A brief background on the literature supporting the PharmGKB pathway about doxorubicin action, and a summary of this active area of research can be found in this paper.
Abstract: The goal of this study is to give a brief background on the literature supporting the PharmGKB pathway about doxorubicin action, and provides a summary of this active area of research. The reader is referred to recent in-depth reviews [1–4] for more detailed discussion of this important and complex pathway. Doxorubicin is an anthracyline drug first extracted from Streptomyces peucetius var. caesius in the 1970’s and routinely used in the treatment of several cancers including breast, lung, gastric, ovarian, thyroid, non-Hodgkin’s and Hodgkin’s lymphoma, multiple myeloma, sarcoma, and pediatric cancers [5–7]. A major limitation for the use of doxorubicin is cardiotoxicity, with the total cumulative dose being the only criteria currently used to predict the toxicity [4,8]. As there is evidence that the mechanisms of anticancer action and of cardiotoxicity occur through different pathways there is hope for the development of anthracycline drugs with equal efficacy but reduced toxicity [4]. Knowledge of the pharmacogenomics of these pathways may eventually allow for future selection of patients more likely to achieve efficacy at lower doses or able to withstand higher doses with lesser toxicity. We present here graphical representations of the candidate genes for the pharmacogenomics of doxorubicin action in a stylized cancer cell (Fig. 1) and toxicity in cardiomyocytes (Fig. 2), and a table describing the key variants examined so far.
Open in a separate window
Fig. 1
Graphical representation of the candidate genes involved in the pharmacodynamics of doxorubicin in a stylized cancer cell. A fully interactive version of this pathway is available online at PharmGKB at http://www.pharmgkb.org/do/serve?objId=PA165292163o ROS, reactive oxygen species.
1,168 citations
TL;DR: This work analyzes key considerations when choosing genome editing agents and identifies opportunities for future improvements and applications in basic research and therapeutics.
Abstract: The development of new CRISPR-Cas genome editing tools continues to drive major advances in the life sciences. Four classes of CRISPR-Cas-derived genome editing agents-nucleases, base editors, transposases/recombinases and prime editors-are currently available for modifying genomes in experimental systems. Some of these agents have also moved rapidly into the clinic. Each tool comes with its own capabilities and limitations, and major efforts have broadened their editing capabilities, expanded their targeting scope and improved editing specificity. We analyze key considerations when choosing genome editing agents and identify opportunities for future improvements and applications in basic research and therapeutics.
1,068 citations
References
More filters
TL;DR: Doxorubicin therapy in childhood impairs myocardial growth in a dose-related fashion and results in a progressive increase in left ventricular afterload sometimes accompanied by reduced contractility, hypothesized to result in inadequateleft ventricular mass and clinically important heart disease in later years.
Abstract: Background. Cardiotoxicity is a recognized complication of doxorubicin therapy, but the long-term effects of doxorubicin are not well documented. We therefore assessed the cardiac status of 115 children who had been treated for acute lymphoblastic leukemia with doxorubicin 1 to 15 years earlier in whom the disease was in continuous remission. Methods. Eighteen patients received one dose of doxorubicin (45 mg per square meter of body-surface area), and 97 received multiple doses totaling 228 to 550 mg per square meter (median, 360). The median interval between the end of treatment and the cardiac evaluation was 6.4 years. Our evaluation consisted of a history, 24-hour ambulatory electrocardiographic recording, exercise testing, and echocardiography. Results. Fifty-seven percent of the patients had abnormalities of left ventricular afterload (measured as end-systolic wall stress) or contractility (measured as the stress—velocity index). The cumulative dose of doxorubicin was the most significant pr...
1,302 citations
Journal Article•
TL;DR: The high intracellular drug accumulation was directly related to the enhancement of the cytotoxicity of the antitumor agents, and the vincristine and Adriamycin resistance in these cells was circumvented.
Abstract: Some calcium antagonists and calmodulin inhibitors enhance the intracellular levels of vincristine and Adriamycin in vincristine- and Adriamycin-resistant P388 leukemia cells by inhibiting their outward transport. The high intracellular drug accumulation was directly related to the enhancement of the cytotoxicity of the antitumor agents, and the vincristine and Adriamycin resistance in these cells was circumvented.
698 citations
TL;DR: The new antitumor agent, adriamycin, is the 14‐hydroxv derivative of daunomyein, which differs from the parent culture by the color of the vegetative and aerial mycelia and by its antibiotics producing ability.
Abstract: Streptomyces peucetius var. caesius, obtained from S. peucetius, the daunomycin producing microorganism, by mutagenic treatment, differs from the parent culture by the color of the vegetative and aerial mycelia and by its antibiotic, producing ability. S. peucetius var. caesius accumulates adriamycin in submerged and aerated culture on a medium containing glucose, brewer's yeast, and inorganic, salts both in shake flasks and in stirred fementers. Isolation of the product is performed by solvent extraction, chromatography on buffered cellulose columns, and crystallization as the hydrochloride. The new antitumor agent, adriamycin, is the 14-hydroxv derivative of daunomyein.
570 citations
TL;DR: P-gly expression occurs in drug-refractory B-cell neoplasms and may contribute to the development of clinical drug resistance, however, other factors, such as the proliferative activity of the tumor, may also play a role in determining response to chemotherapy.
Abstract: The B-cell neoplasms, multiple myeloma and non-Hodgkin's lymphoma, frequently become drug resistant, despite initial responses to chemotherapeutic drugs. Tumor cells from eight patients with clinically drug-refractory disease were evaluated by immuno-histochemical staining for monoclonal immunoglobulin (Ig) expression, nuclear proliferation antigen, P-glycoprotein (P-gly) expression, and other cellular antigens. P-gly was detected on tumor cells from six of eight patients with drug-resistant disease. Of the six patients with P-gly-positive tumors, five patients had advanced multiple myeloma and one had a drug-refractory non-Hodgkin's lymphoma. Cellular RNA analysis confirmed the over-expression of P-gly. In an effort to overcome drug resistance, a pilot study evaluated possible verapamil enhancement of chemotherapy in these eight patients. All patients had developed progressive disease while receiving a regimen containing vincristine and doxorubicin, and seven of eight patients had previously received continuous infusion vincristine and doxorubicin plus oral dexamethasone (VAD). At the time of progressive disease, continuous infusion verapamil was added to the VAD regimen. Three of the eight patients who were refractory to vincristine and doxorubicin alone responded when verapamil was added to VAD. The three patients who responded had P-gly-positive tumors. Verapamil increased the intracellular accumulation of doxorubicin and vincristine in vitro for both a P-gly-positive myeloma cell line and tumor cells from two patients with end-stage myeloma which over-expressed P-gly. The dose-limiting side effect associated with the addition of verapamil to chemotherapy was temporary impairment of cardiac function, manifest as hypotension and cardiac arrhythmia. We conclude that P-gly expression occurs in drug-refractory B-cell neoplasms and may contribute to the development of clinical drug resistance. However, other factors, such as the proliferative activity of the tumor, may also play a role in determining response to chemotherapy. The administration of verapamil along with VAD chemotherapy may partially circumvent drug resistance in patients whose tumors over-express P-gly.
566 citations
TL;DR: Free radical-independent cytotoxicity mechanisms, taking place in the nuclear compartment of the cell, may more likely be involved in the antitumor effect of doxorubicin.
500 citations