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The Oncologist Nov 2020Studies targeting cladribine in combination with granulocyte colony-stimulating factor, low-dose cytarabine, and aclarubicin (C-CAG) regimen in relapsed and refractory...
LESSONS LEARNED
Studies targeting cladribine in combination with granulocyte colony-stimulating factor, low-dose cytarabine, and aclarubicin (C-CAG) regimen in relapsed and refractory acute myeloid leukemia (R/R AML) are limited. The complete remission rate after two cycles of C-CAG regimen was 67.6%, and 1-year overall survival and disease-free survival rates were 59.7% and 72.9%, respectively. The C-CAG regimen is significantly effective against R/R AML with a low hematological toxicity and thus serves as an alternative treatment for R/R AML.
BACKGROUND
The optimal salvage chemotherapy regimen for relapsed and refractory acute myeloid leukemia (R/R AML) remains uncertain. Therefore, a phase II study was conducted for the prospective evaluation of the efficacy and safety of the purine analog cladribine in combination with granulocyte colony-stimulating factor (G-CSF), low-dose cytarabine, and aclarubicin (C-CAG) regimen for patients with R/R AML.
METHODS
A total of 34 patients received C-CAG regimen for salvage treatment as follows: cladribine 5 mg/m , days 1-5; G-CSF 300 μg, days 0-9; aclarubicin 10 mg, days 3-6; cytarabine 10 mg/m every 12 hours, subcutaneously, days 3-9; 4 weeks per cycle. Patients were allowed to withdraw from the study if complete remission (CR) was not achieved after two courses of chemotherapy. If conditions were right, the patients achieving CR were recommended to receive allogeneic hematopoietic stem cell transplantation. Otherwise, they were treated for a total of six cycles unless disease progression or unacceptable side effects were observed or they withdrew their consent.
RESULTS
All patients received at least two cycles of C-CAG regimen chemotherapy. After two cycles of C-CAG, 23 patients (67.6%) achieved CR, and 5 patients had partial remission (14.7%). At a median follow-up of 15 months (range, 3-38 months), the 1-year overall survival (OS) and disease-free survival (DFS) rates were 59.7% (95% confidence interval [CI], 42.6%-76.8%) and 72.9% (95% CI, 54.3%-91.5%), respectively. The most common adverse effect was myelosuppression. Nonhematological toxicities were mild, and no treatment-related deaths occurred.
CONCLUSION
Preliminary data indicate that the C-CAG regimen chemotherapy is significantly effective against R/R AML with a high remission rate and a low hematological toxicity. Thus, it may serve as an alternative treatment for R/R AML.
Topics: Aclarubicin; Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cladribine; Cytarabine; Female; Granulocyte Colony-Stimulating Factor; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Prospective Studies; Treatment Outcome; Young Adult
PubMed: 32845551
DOI: 10.1634/theoncologist.2020-0818 -
International Journal of Hyperthermia :... 2022Thermosensitive liposomes (TSL) and other triggered drug delivery systems (DDS) are promising therapeutic strategies for targeted drug delivery. However, successful...
OBJECTIVE
Thermosensitive liposomes (TSL) and other triggered drug delivery systems (DDS) are promising therapeutic strategies for targeted drug delivery. However, successful designs with candidate drugs depend on many variables, including nanoparticle formulation, drug properties, and cancer cell properties. We developed a computational model based on experimental data to predict the potential efficacies of drugs when used with triggered DDS, such as TSL.
METHODS
A computer model based on the Krogh cylinder was developed to predict uptake and cell survival with four anthracyclines when delivered by intravascular triggered DDS (e.g., TSL): doxorubicin (DOX), idarubicin (IDA), pirarubicin (PIR), and aclarubicin (ACLA). We simulated three tumor types derived from SVR angiosarcoma, LLC lung cancer, or SCC-1 oral carcinoma cells. cellular drug uptake and cytotoxicity data were obtained experimentally and incorporated into the model.
RESULTS
For all three cell lines, ACLA and IDA had the fastest cell uptake, with slower uptake for DOX and PIR. Cytotoxicity was highest for IDA and lowest for ACLA. The computer model predicted the highest tumor drug uptake for ACLA and IDA, resulting from their rapid cell uptake. Overall, IDA was most effective and produced the lowest tumor survival fraction, with DOX being the second best. Perivascular drug penetration was reduced for drugs with rapid cell uptake, potentially limiting delivery to cancer cells distant from the vasculature.
CONCLUSION
Combining simple experiments with a computer model could provide a powerful screening tool to evaluate the potential efficacy of candidate investigative drugs preceding TSL encapsulation and studies.
Topics: Antibiotics, Antineoplastic; Cell Line, Tumor; Doxorubicin; Drug Delivery Systems; Liposomes; Nanoparticles
PubMed: 35876089
DOI: 10.1080/02656736.2022.2086303 -
Medicine Mar 2023This study aimed to explore the effects of recombinant human thrombopoietin (rhTPO) on platelet recovery in decitabine, cytarabine, aclarubicin, and G-CSF (DCAG)-treated...
BACKGROUND
This study aimed to explore the effects of recombinant human thrombopoietin (rhTPO) on platelet recovery in decitabine, cytarabine, aclarubicin, and G-CSF (DCAG)-treated patients with intermediate-high-risk myelodysplastic syndrome/hypo proliferative acute myeloid leukemia.
METHODS
Recruited patients were at a ratio of 1:1 into 2 groups: the rhTPO group (DCAG + rhTPO) and control group (DCAG). The primary endpoint was the time for platelets to recover to ≥ 20 × 109/L. The secondary endpoints were the time for platelets to recover to ≥ 30 × 109/L and ≥ 50 × 109/L, overall survival (OS), and progression-free survival (PFS).
RESULTS
The time required for platelet recovery to ≥ 20 × 109/L, ≥30 × 109/L, and ≥ 50 × 109/L in the rhTPO group was significantly shorter (6.5 ± 2.2 vs 8.4 ± 3.1 days, 9.0 ± 2.7 vs 12.2 ± 3.9 days, 12.4 ± 4.7 vs 15.5 ± 9.3 days, respectively; all P < .05 vs controls). The amount of platelet transfusion in the rhTPO group was smaller (4.4 ± 3.1 vs 6.1 ± 4.0 U, P = .047 vs controls). The bleeding score was lower (P = .045 vs controls). The OS and PFS were significantly different (P = .009 and P = .004). The multivariable analysis showed that age, karyotype, and time for PLT recovery to ≥ 20 × 109/L were independently associated with OS. Adverse events were similar.
CONCLUSIONS
This study suggests that rhTPO leads to a faster platelet recovery after DCAG treatment, reduces the risk of bleeding, reduces the number of platelet transfusions, and prolongs the OS and PFS.
Topics: Humans; Thrombopoietin; Blood Platelets; Recombinant Proteins; Myelodysplastic Syndromes; Leukemia, Myeloid, Acute
PubMed: 37000082
DOI: 10.1097/MD.0000000000033373 -
Endocrine-related Cancer Jun 2013Adrenocortical carcinoma (ACC) is a rare but aggressive malignancy with no effective therapy for patients with unresectable disease. The aim of the current study was i)...
Adrenocortical carcinoma (ACC) is a rare but aggressive malignancy with no effective therapy for patients with unresectable disease. The aim of the current study was i) to evaluate TOP2A expression and function in human adrenocortical neoplasm and ACC cells and ii) to determine the anticancer activity of agents that target TOP2A. TOP2A mRNA and protein expression levels were evaluated in 112 adrenocortical tissue samples (21 normal adrenal cortex, 80 benign adrenocortical tumors, and 11 ACCs). In vitro siRNA knockdown of TOP2A in ACC cell lines (NCI-H295R and SW13) was used to determine its effect on cellular proliferation, cell cycle, anchorage-independent growth, and cellular invasion. We screened 14 TOP2A inhibitors for their anticancer activity in ACC cells. TOP2A mRNA and protein expression was significantly higher in ACC than in benign and normal adrenocortical tissue samples (P<0.05). Knockdown of TOP2A gene expression in ACC cell lines significantly decreased cell proliferation, anchorage-independent growth, and invasion (P<0.05). A screening assay in NCI-H295R cells showed that 11 of 14 TOP2A inhibitors had antiproliferative activity, 5 of the 14 TOP2A inhibitors had a higher antiproliferative activity than mitotane, and aclarubicin was the agent with the highest activity. Aclarubicin was validated to significantly decrease proliferation and tumor spheroid size in both NCI-H295R and SW13 ACC cell lines (P<0.05). Our results suggest that TOP2A is overexpressed in ACC, regulates cellular proliferation and invasion in ACC cells, and is an attractive target for ACC therapy. Of the TOP2A inhibitors screened, aclarubicin is a good candidate agent to test in future clinical trials for patients with locally advanced and metastatic ACC.
Topics: Aclarubicin; Adrenal Cortex Neoplasms; Adrenocortical Carcinoma; Antigens, Neoplasm; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; DNA Topoisomerases, Type II; DNA-Binding Proteins; Gene Knockdown Techniques; Humans; Poly-ADP-Ribose Binding Proteins; RNA, Messenger; RNA, Small Interfering; Topoisomerase II Inhibitors
PubMed: 23533247
DOI: 10.1530/ERC-12-0403 -
Clinical Epigenetics Sep 2020Epigenetic mechanisms play an important role in the chemoresistance of acute myeloid leukemia (AML). The clinical response to epigenetic modifier-based chemotherapy in...
Chidamide, decitabine, cytarabine, aclarubicin, and granulocyte colony-stimulating factor (CDCAG) in patients with relapsed/refractory acute myeloid leukemia: a single-arm, phase 1/2 study.
BACKGROUND
Epigenetic mechanisms play an important role in the chemoresistance of acute myeloid leukemia (AML). The clinical response to epigenetic modifier-based chemotherapy in patients with relapsed/refractory AML (r/r AML) is unclear. This multicenter clinical trial evaluated the safety and efficacy of epigenetic modifiers (chidamide and decitabine) in combination with aclarubicin, cytarabine, and granulocyte colony-stimulating factor (G-CSF) in patients with r/r AML.
RESULTS
Adult patients with r/r AML were treated with chidamide, decitabine, cytarabine, aclarubicin, and G-CSF (CDCAG). The primary measures were overall response (OR), overall survival (OS), and safety. Next-generation sequencing was performed to analyze the correlation between gene mutations and response. A total of 93 patients with r/r AML were enrolled. Overall, 24 patients had a complete remission (CR) and 19 patients achieved CR with incomplete blood count recovery (CRi). The overall response rate (ORR) was 46.2%. The overall survival of these 43 patients who achieved CR/CRi was significantly longer than that of patients who failed to achieve remission (563 vs 152 days, P < 0.0001). Of the patients with mutations in epigenetic and transcription factor-related genes, but without internal tandem duplications in FMS-like tyrosine kinase3 (FLT3-ITDs), 55.6% achieved CR/CRi, whereas the ORR was 28.2% for patients with mutations in other genes.
CONCLUSIONS
The CDCAG regimen was well tolerated and effective in r/r AML. Patients with epigenetic and transcription factor-related gene mutations, but without FLT3-ITD mutations, may benefit from this regimen.
TRIAL REGISTRATION
Clinical Trials, NCT02886559 . Registered 01 September 2016.
Topics: Aclarubicin; Adolescent; Adult; Aminopyridines; Antibiotics, Antineoplastic; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Cytarabine; Decitabine; Disease-Free Survival; Female; Granulocyte Colony-Stimulating Factor; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Remission Induction; Treatment Outcome; Young Adult
PubMed: 32873343
DOI: 10.1186/s13148-020-00923-4 -
OncoTargets and Therapy 2023The prognosis of patients with unfit or relapsed/refractory (R/R) AML remains poor. Venetoclax (VEN) has been shown to exhibit anti-leukemia stem cell activity; however,...
PURPOSE
The prognosis of patients with unfit or relapsed/refractory (R/R) AML remains poor. Venetoclax (VEN) has been shown to exhibit anti-leukemia stem cell activity; however, few studies have been published on the efficacy and safety of VEN combined with both hypomethylating agents (HMAs) and low-dose chemotherapy for patients with unfit or R/R AML.
METHODS
This study retrospectively analyzed the clinical characteristics, treatment details, safety profile and clinical outcomes of patients with unfit or R/R AML treated with VEN+ HMAs+ half-dose CAG (LDAC, aclarubicin and granulocyte colony-stimulating factor).
RESULTS
A total of 24 AML patients were involved in the study, of whom 13 (54.2%) were in the unfit group, and 11 (45.8%) were in the R/R group. and (8/24, 33.3%) were the most common gene aberrations. Patients in the R/R group were found to be more likely to carry (5/11, 45.5%) compared with the unfit group (0/13, 0%) ( = 0.006). The ORR observed during the study was 83.3% (20/24; 14 CR, 2CRi, 4PR). In the unfit group, 11/13 (84.6%) patients achieved cCR (10 CR and 1 CRi); while 5/11 (45.5%) R/R patients achieved response (4 CR and 1 CRi). CR was observed in all AML patients with (5/5), (3/3), (3/3) and (3/3). The most common adverse events (AEs) during VEN+ HMAs+ half-dose CAG therapy were persistent cytopenias and infections.
CONCLUSION
The results of this study confirm that VEN+ HMAs+ half-dose CAG is associated with promising efficacy (even high-risk molecular patterns) and tolerable safety profile in patients with unfit or R/R AML. Yet, the study involves only a small sample size, which should not be overlooked. As such, further studies on the efficacy of VEN combined with HMAs and half-dose CAG regimen in AML patients are essential.
PubMed: 37334144
DOI: 10.2147/OTT.S405611 -
OncoTargets and Therapy 2023We performed sequential molecular analyses of a 75-year-old woman with -ITD positive acute myeloid leukemia (AML) who had received gilteritinib therapy for 43 months. At...
Gilteritinib Affects the Selection of Dominant Clones in Clonal Hematopoiesis: Sequential Genetic Analysis of an -ITD Positive AML Patient with Long-Term Gilteritinib Therapy.
We performed sequential molecular analyses of a 75-year-old woman with -ITD positive acute myeloid leukemia (AML) who had received gilteritinib therapy for 43 months. At the time of diagnosis, her karyotype was normal; however, -ITD, , and mutations were detected. She received induction therapy with daunorubicin and cytarabine and achieved hematological complete remission (HCR). After attaining HCR, she underwent consolidation therapy with azacytidine or cytarabine, aclarubicin, and granulocyte-colony stimulating factor. However, AML relapsed eight months after the first HCR. -ITD and mutations were persistently positive, and the patient received gilteritinib therapy. Although the -ITD clone was not detected during gilteritinib treatment, a clone harboring monosomy 7 and mutations emerged. Bone marrow examinations at 15, 24, and 32 months after gilteritinib treatment revealed multi-lineage blood cell dysplasia without an increase in myeloblasts. After 33 months of treatment, gilteritinib was discontinued for two months because to ileus development, and the -ITD clone was detected again. Gilteritinib treatment was restarted, and -ITD became negative. Our analysis demonstrated that: (1) hematopoiesis derived from gilteritinib-resistant clones was generated by long-term gilteritinib treatment, and (2) -ITD clones regained clonal dominance in the absence of FLT3 inhibition. These findings suggest that gilteritinib affects the selection of dominant clones during clonal hematopoiesis.
PubMed: 37465589
DOI: 10.2147/OTT.S417137 -
Aging Apr 2020We evaluated the risk status and survival outcomes of 125 elderly acute myeloid leukemia (AML) patients treated with decitabine in combination with low-dose cytarabine,...
We evaluated the risk status and survival outcomes of 125 elderly acute myeloid leukemia (AML) patients treated with decitabine in combination with low-dose cytarabine, aclarubicin, and G-CSF (D-CAG). The risk status was evaluated by determining the frequency of recurring gene mutations using next-generation sequencing (NGS) analysis of 23 selected genes and cytogenetic profiling of bone marrow samples at diagnosis. After a median follow-up of 12 months (range: 2-82 months), 86 patients (68.8%) had achieved complete remission after one cycle of induction, and 94 patients (75.2%) had achieved it after two cycles. The median overall survival (OS) and disease-free survival (DFS) were 16 and 12 months, respectively. In 21 AML patients aged above 75 years, the median OS and DFS were longer in the low- and intermediate-risk group than the high-risk group, but the differences were not statistically significant. The median OS and DFS were similar in patients with or without , , and mutations. Multivariate analysis showed that patient age above 75 years, high-risk status, and genetic anomalies, like deletions in chromosomes 5 and/or 7, were significant variables in predicting OS. D-CAG regimen tends to improve the prognosis of a subgroup of elderly patients with high-risk AML.
Topics: Aclarubicin; Age Factors; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Decitabine; Disease-Free Survival; Female; Granulocyte Colony-Stimulating Factor; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Prognosis; Survival Rate; Treatment Outcome
PubMed: 32238611
DOI: 10.18632/aging.102973 -
Malaria Journal Jul 2022Plasmodium falciparum has been becoming resistant to the currently used anti-malarial drugs. Searching for new drug targets is urgently needed for anti-malarial...
BACKGROUND
Plasmodium falciparum has been becoming resistant to the currently used anti-malarial drugs. Searching for new drug targets is urgently needed for anti-malarial development. DNA helicases separating double-stranded DNA into single-stranded DNA intermediates are essential in nearly all DNA metabolic transactions, thus they may act as a candidate for new drug targets against malarial parasites.
METHODS
In this study, a P. falciparum 5' to 3' DNA helicase (PfDH-B) was partially purified from the crude extract of chloroquine- and pyrimethamine-resistant P. falciparum strain K1, by ammonium sulfate precipitation and three chromatographic procedures. DNA helicase activity of partially purified PfDH-B was examined by measuring its ability to unwind P-labelled partial duplex DNA. The directionality of PfDH-B was determined, and substrate preference was tested by using various substrates. Inhibitory effects of DNA intercalators such as anthracycline antibiotics on PfDH-B unwinding activity and parasite growth were investigated.
RESULTS
The native PfDH-B was partially purified with a specific activity of 4150 units/mg. The PfDH-B could unwind M13-17-mer, M13-31-mer with hanging tail at 3' or 5' end and a linear substrate with 3' end hanging tail but not blunt-ended duplex DNA, and did not need a fork-like substrate. Anthracyclines including aclarubicin, daunorubicin, doxorubicin, and nogalamycin inhibited the unwinding activity of PfDH-B with an IC value of 4.0, 7.5, 3.6, and 3.1 µM, respectively. Nogalamycin was the most effective inhibitor on PfDH-B unwinding activity and parasite growth (IC = 0.1 ± 0.002 µM).
CONCLUSION
Partial purification and characterization of 5'-3' DNA helicase of P. falciparum was successfully performed. The partially purified PfDH-B does not need a fork-like substrate structure found in P. falciparum 3' to 5' DNA helicase (PfDH-A). Interestingly, nogalamycin was the most potent anthracycline inhibitor for PfDH-B helicase activity and parasite growth in culture. Further studies are needed to search for more potent but less cytotoxic inhibitors targeting P. falciparum DNA helicase in the future.
Topics: Anthracyclines; Antimalarials; DNA; DNA Helicases; Humans; Malaria, Falciparum; Nogalamycin; Plasmodium falciparum
PubMed: 35821133
DOI: 10.1186/s12936-022-04238-y -
Cancer Chemotherapy and Pharmacology 1993Aclarubicin is an anthracycline antibiotic that differs from doxorubicin in its structure, mechanism of action, and preclinical toxicity profile, especially its reduced... (Clinical Trial)
Clinical Trial
Aclarubicin is an anthracycline antibiotic that differs from doxorubicin in its structure, mechanism of action, and preclinical toxicity profile, especially its reduced cardiotoxicity. We therefore conducted a side-by-side in vivo and in vitro trial of this agent in metastatic breast-cancer patients and their biopsied tumor specimens, respectively. Aclarubicin (100 mg/m2) was given by intravenous infusion every 3 weeks to 22 patients with objectively measurable metastatic breast cancer, 15 of whom had not previously received doxorubicin. The dose-limiting toxicity consisted primarily of leukopenia and severe nausea and vomiting. No objective response was observed in the 19 evaluable patients. After disease progression, 10 of the 15 doxorubicin-naive patients were treated with doxorubicin; 6 patients achieved a partial response, including 4 who responded to doxorubicin alone and 2 who responded to doxorubicin in combination with thiotepa and vinblastine. Tumor specimens were obtained from 14 of the 22 patients prior to the start of therapy and were tested for in vitro sensitivity to aclarubicin and doxorubicin using a soft agar colony-forming assay. Adequate colony growth occurred in 9 of 14 cultured tumor specimens. All 9 specimens, including 3 obtained from doxorubicin-naive patients, demonstrated in vitro resistance to aclarubicin. In all, 1 of 3 specimens taken from doxorubicin-naive patients demonstrated in vitro sensitivity to doxorubicin, whereas 6 tumor specimens obtained from patients who had undergone prior doxorubicin therapy demonstrated in vitro resistance. The patient whose tumor demonstrated in vitro doxorubicin sensitivity responded to a doxorubicin regimen after failing aclarubicin treatment; in vitro doxorubicin resistance correlated with clinical resistance in all cases. We conclude that aclarubicin is inactive in metastatic breast cancer at the dose and schedule used. Side-by-side in vivo and in vitro trials are feasible and could be useful in the development of investigational agents with activity greater than that of aclarubicin and, particularly, in the evaluation of analogs of clinically active drugs.
Topics: Aclarubicin; Adult; Aged; Breast Neoplasms; Doxorubicin; Drug Resistance; Female; Humans; In Vitro Techniques; Middle Aged; Neoplasm Metastasis; Treatment Outcome; Tumor Stem Cell Assay
PubMed: 8453689
DOI: 10.1007/BF00685040