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Drug Design, Development and Therapy 2018Despite available therapies after initial systemic therapy, prognosis remains poor in relapsed or refractory soft tissue sarcomas (STS). The rational and clinical... (Review)
Review
Despite available therapies after initial systemic therapy, prognosis remains poor in relapsed or refractory soft tissue sarcomas (STS). The rational and clinical development of novel agents to improve outcomes in this area of high unmet need is desperately warranted. Aldoxorubicin is a prodrug of doxorubicin that binds to serum albumin immediately after administration through an acid-sensitive hydrazone linker and is subsequently transported to tumor tissues where the acidic environment cleaves the linker and facilitates delivery of a tumor-targeted drug payload. In clinical studies to date, there has been evidence of efficacy and mitigated cardiac toxicity. In this review, we comprehensively detail the clinical development of aldoxorubicin in STS to date. Specifically, we highlight available data on the pharmacokinetics and efficacy from Phase I, Phase II, and Phase III trials in advanced or metastatic STS. We conclude with considerations for future directions of investigation for this promising antitumor agent.
Topics: Antineoplastic Agents; Doxorubicin; Humans; Hydrazones; Sarcoma
PubMed: 29670334
DOI: 10.2147/DDDT.S140638 -
Methods in Molecular Biology (Clifton,... 2023Liposome-mediated anticancer drug delivery has the advantage of limiting the massive cytotoxicity of chemotherapeutic agents. Doxorubicin (DOX) PEG-liposomal does...
Liposome-mediated anticancer drug delivery has the advantage of limiting the massive cytotoxicity of chemotherapeutic agents. Doxorubicin (DOX) PEG-liposomal does however have a slow-release rate that hinders its therapeutic efficacy. In this study, an integrated therapeutic system based on magnetic thermosensitive liposomes was designed. The chelated gadolinium acquired magnetic properties in the liposomes. The hyperthermia induced by ultra-high-field magnetic resonance imaging (UHF-MRI) enhances the chemotherapeutic effects of DOX. The DOX release from liposomes was facilitated over a narrow range of temperatures owing to the phase transition temperature of the liposomes. The magnetic properties of the liposomes were evident by the elevation of contrast after the exposure to UHF-MRI. Moreover, triple-negative breast cancer (TNBC) cells showed a significant decrease in cellular viability reaching less than 40% viability after 1 h of exposure to UHF-MRI. The liposomes demonstrated a physiological coagulation time and a minimal hemolytic potential in hemocompatibility studies; therefore, they were considered safe for physiological application. As a result, magnetic-thermosensitive liposomal guidance of local delivery of DOX could increase the therapeutic index, thereby reducing the amount of the drug required for systemic administration and the chance of affecting the adjacent tissues.
Topics: Liposomes; Cell Line, Tumor; Doxorubicin; Antineoplastic Agents; Drug Delivery Systems
PubMed: 36781754
DOI: 10.1007/978-1-0716-2954-3_9 -
The Journal of Pharmacy and Pharmacology Jun 2016The use of doxorubicin, a drug utilised for many years to treat a wide variety of cancers, has long been limited due to the significant toxicity that can occur not only... (Review)
Review
OBJECTIVES
The use of doxorubicin, a drug utilised for many years to treat a wide variety of cancers, has long been limited due to the significant toxicity that can occur not only during, but also years after treatment. It has multiple mechanisms of action including the intercalation of DNA, inhibition of topoisomerase II and the production of free radicals. We review the literature, with the aim of highlighting the role of drug concentration being an important determinant on the unfolding cell biological events that lead to cell stasis or death.
METHODS
The PubMed database was consulted to compile this review.
KEY FINDINGS
It has been found that the various mechanisms of action at the disposal of doxorubicin culminate in either cell death or cell growth arrest through various cell biological events, such as apoptosis, autophagy, senescence and necrosis. Which of these events is the eventual cause of cell death or growth arrest appears to vary depending on factors such as the patient, cell and cancer type, doxorubicin concentration and the duration of treatment.
CONCLUSIONS
Further understanding of doxorubicin's influence on cell biological events could lead to an improvement in the drug's efficacy and reduce toxicity.
Topics: Animals; Antibiotics, Antineoplastic; Apoptosis; Autophagy; Cell Proliferation; Cellular Senescence; Dose-Response Relationship, Drug; Doxorubicin; Energy Metabolism; Humans; Necrosis; Neoplasms; Time Factors; Topoisomerase II Inhibitors
PubMed: 26989862
DOI: 10.1111/jphp.12539 -
BMC Cancer Nov 2020The recommended cumulative doxorubicin dose in soft tissue sarcoma (STS) treatment was based on cardiotoxicity data from retrospective studies of breast cancer patients....
BACKGROUND
The recommended cumulative doxorubicin dose in soft tissue sarcoma (STS) treatment was based on cardiotoxicity data from retrospective studies of breast cancer patients. However, the treatment and prognosis of STS and breast cancer are quite different, and reference to breast cancer data alone may not reflect the efficacy of doxorubicin treatment in STS. This study, thus, aimed to review and analyze clinical data of STS patients treated with a high cumulative doxorubicin dose, to provide a reference for treatment selection and clinical trial design.
METHODS
We retrospectively collected and analyzed clinical data of patients with advanced STS who received doxorubicin-based chemotherapy from January 2016 to January 2020. The patients were divided into a standard-dose group (who received ≤6 cycles of doxorubicin after the initial diagnosis) and an over-dose group (who were re-administered doxorubicin [doxorubicin-rechallenge] after receiving 6 cycles of doxorubicin therapy discontinuously). Patient characteristics, cumulative doxorubicin dose, objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), cardiotoxicity incidence, and treatment effectiveness were evaluated in both groups.
RESULTS
A total of 170 patients with advanced STS were recruited (146 in the standard-dose group and 24 in the over-dose group). The average cumulative doxorubicin dose was 364.04 ± 63.81 mg/m2 in the standard-dose group and 714.38 ± 210.09 mg/m2 in the over-dose group. The ORR, DCR, and median PFS were 15.07, 58.9%, and 6 (95% confidence interval [CI]: 5.8-6.5) months in the standard-dose group and 16.67, 66.67%, and 4 (95%CI: 2.0-5.8) months in the over-dose group, respectively. Symptomatic heart failure occurred in five patients (3.42%) of the standard-dose group and in one patient (4.17%) of the over-dose group. In these patients with cardiotoxicity, doxorubicin was discontinued, and all of them died of uncontrolled tumor growth. No drug-related deaths occurred.
CONCLUSIONS
The continuation of or rechallenge with doxorubicin beyond the recommended cumulative dose could be a promising therapeutic option in the treatment of chemotherapy-sensitive advanced sarcomas. Further evaluation is necessary in prospective trials.
Topics: Antibiotics, Antineoplastic; Doxorubicin; Female; Humans; Male; Sarcoma
PubMed: 33228579
DOI: 10.1186/s12885-020-07663-x -
Carbohydrate Polymers May 2021Doxorubicin (DOX), an anthracycline drug, is widely used for the treatment of several cancers like osteosarcoma, cervical carcinoma, breast cancer, etc. DOX lacks target... (Review)
Review
Doxorubicin (DOX), an anthracycline drug, is widely used for the treatment of several cancers like osteosarcoma, cervical carcinoma, breast cancer, etc. DOX lacks target specificity; thereby it also affects normal cells thus resulting in several side-effects. A drug delivery system (DDS) can be used to deliver the drug in a controlled and sustained manner at a targeted site within the body. Various DDS like nanoemulsions, polymeric nanoparticles, and liposomes are used for loading DOX. Alginate, a polysaccharide is widely used for fabricating DDS due to its biodegradable and bio-compatible properties. Alginates, in combination with other biomaterials, have been extensively used as a novel drug delivery carrier for DOX. Alginate provides a platform for drug delivery in different forms like hydrogels, nanogels, nanoparticles, microparticles, graphene oxide systems, magnetic systems, etc. Herein, we briefly describe alginate in combination with other materials as a nanocarrier for targeted delivery of DOX for anti-cancer treatment.
Topics: Alginates; Animals; Antibiotics, Antineoplastic; Cell Survival; Doxorubicin; Drug Carriers; Humans; Hydrogels; Nanogels; Neoplasms
PubMed: 33673985
DOI: 10.1016/j.carbpol.2021.117696 -
Biochimica Et Biophysica Acta. General... Dec 2020Vascular endothelial growth factor (VEGF), is upregulated in tumor cells and thus became a potential therapeutic target for anti-cancer drugs. Recent reports suggested...
BACKGROUND
Vascular endothelial growth factor (VEGF), is upregulated in tumor cells and thus became a potential therapeutic target for anti-cancer drugs. Recent reports suggested the use of Doxorubicin (Dox) with VEGF-targeting siRNAs for an enhanced decrease in VEGF expression. Besides, VEGF-B gene therapy was found to suppress the cardiotoxicity effects of Dox. On the other hand, even though Dox is a commonly used anti-cancer agent, its mechanism of actions isn't completely mapped out. Herein, the interactions between a G4 structure formed by the VEGF promoter region Pu and Dox were investigated.
METHODS
The Dox-G4 interactions were examined via competition dialysis, UV-vis Absorption, Circular Dichroism (CD) and Fluorescence spectroscopy.
RESULTS
The results demonstrated that Dox was stabilizing the VEGF Pu G4 structure and the calculated association constant for VEGF Pu-G4 complex (K = 7.50 × 10) was very close to the reported K values for Dox-dsDNA complexes. Additionally, the competition dialysis experiments revealed the selectivity of Dox to Pu compared to other G4 structures formed in telomeric repeats and promoter regions such as BCL-2 and C-myc.
CONCLUSIONS
Dox exhibits strong and selective association with VEGF Pu G4 structure that was comparable to its well-known association with dsDNA.
GENERAL SIGNIFICANCE
The results presented here might be useful in the general area of antitumor drug-DNA interactions. Doxorubicin's significant affinity to VEGF Pu G4 might be one of the plausible mechanisms behind its anti-tumor activity.
Topics: Antibiotics, Antineoplastic; Doxorubicin; G-Quadruplexes; Humans; Neoplasms; Promoter Regions, Genetic; Vascular Endothelial Growth Factor A
PubMed: 32860839
DOI: 10.1016/j.bbagen.2020.129720 -
Drug Intelligence & Clinical Pharmacy Apr 1985The long-term therapeutic potential of doxorubicin is often limited by the predictable development of a dose-related cardiomyopathy. Empiric limitations of cumulative... (Review)
Review
The long-term therapeutic potential of doxorubicin is often limited by the predictable development of a dose-related cardiomyopathy. Empiric limitations of cumulative doses to 450-550 mg/m2 minimize the incidence of this potentially fatal toxicity. This review presents recent studies performed to examine the potential for altered dose schedule to reduce or delay this toxicity and maintain therapeutic efficacy. Altering doxorubicin's dosing schedule from the standard three-weekly regimen to a continuous infusion or weekly schedule has been shown to delay cardiotoxicity. Data presented suggest that doxorubicin administered on a weekly schedule significantly reduces cardiotoxicity as compared with a three-weekly schedule and allows approximately 160 mg/m2 more of the drug to be administered to reach the same level of cardiotoxicity as measured by endomyocardial biopsy. This corresponds clinically to two additional months of therapy. Cumulated response data suggest that continuous infusion or weekly schedules of doxorubicin are equally efficacious as the standard three-weekly schedule.
Topics: Doxorubicin; Drug Administration Schedule; Half-Life; Heart Diseases; Humans; Kinetics; Neoplasms
PubMed: 3891276
DOI: 10.1177/106002808501900403 -
Cancer Treatment Reviews Jul 1993
Comparative Study Review
Topics: Antineoplastic Combined Chemotherapy Protocols; Doxorubicin; Epirubicin; Humans; Neoplasms
PubMed: 8334677
DOI: 10.1016/0305-7372(93)90036-q -
Carbohydrate Polymers Aug 2023Breast cancer is one of the most threatening cancers that poses a great risk to women's health. The anti-tumor drug doxorubicin (DOX) is one of commonly used drugs in...
Breast cancer is one of the most threatening cancers that poses a great risk to women's health. The anti-tumor drug doxorubicin (DOX) is one of commonly used drugs in the treatment of breast cancer. However, the cytotoxicity of DOX has always been an urgent challenge to be solved. In this study, we report an alternative drug delivery system delivering DOX for reducing its physiological toxicity by using the yeast β-glucan particle (YGP) with a hollow and porous vesicle structure. Briefly, amino groups were grafted onto the surface of YGP with the silane coupling agent, then the oxidized hyaluronic acid (OHA) was attached by Schiff base reaction to get HA-modified YGP (YGP@N=C-HA), finally DOX was encapsulated into YGP@N=C-HA to get DOX-loaded YGP@N=C-HA (YGP@N=C-HA/DOX). In vitro release experiments exhibited the pH-responsive DOX release from YGP@N=C-HA/DOX. Cell experiments displayed that YGP@N=C-HA/DOX had good killing effect on both MCF-7 and 4T1 cells and could be internalized into these cells through CD44 receptors, showing targetability to cancer cells. Furthermore, YGP@N=C-HA/DOX could effectively inhibit tumor growth and reduce the physiological toxicity of DOX. Thus, the YGP-based vesicle provides an alternative strategy for lowering the physiological toxicity of DOX in the medical treatment of breast cancer.
Topics: Female; Humans; Breast Neoplasms; Hyaluronic Acid; Saccharomyces cerevisiae; beta-Glucans; Doxorubicin; Drug Delivery Systems; Nanoparticles; MCF-7 Cells
PubMed: 37173014
DOI: 10.1016/j.carbpol.2023.120907 -
European Journal of Cancer & Clinical... May 1989The risk of congestive heart failure restricts the clinical use of doxorubicin to cumulative doses of 450-550 mg/m2, when it is given using high-dose rapid intravenous... (Review)
Review
The risk of congestive heart failure restricts the clinical use of doxorubicin to cumulative doses of 450-550 mg/m2, when it is given using high-dose rapid intravenous application. As the high peak serum levels which follow rapid administration seem to be correlated with cardiotoxicity, application schedules leading to lower peak serum concentrations have been developed. This paper reviews the influence of those schedules on cardiotoxicity, non-cardiac toxicities, pharmacokinetic data and antineoplastic efficacy. While the reduction of cardiotoxicity by long-term application schedules is well documented, much less can be said about the antitumor effect of those schedules. Controlled studies dealing with this problem are needed. This review provides a base for that purpose.
Topics: Doxorubicin; Drug Administration Schedule; Heart Diseases; Humans
PubMed: 2661240
DOI: 10.1016/0277-5379(89)90135-1