-
Journal of Biomolecular Structure &... 2023Natural products have emerged as major leads for the discovery and development of new anti-cancer drugs. The plant-derived anti-cancer drugs account for approximately... (Review)
Review
Natural products have emerged as major leads for the discovery and development of new anti-cancer drugs. The plant-derived anti-cancer drugs account for approximately 60% and the quest for new anti-cancer agents is in progress. Anti-cancer leads have been isolated from plants, animals, marine organisms, and microorganisms from time immemorial. The process of semisynthetic modifications of the parent lead has led to the generation of new anti-cancer agents with improved therapeutic efficacy and minimal side effects. The various chemo-informatics tools, bioinformatics, high-throughput screening, and combinatorial synthesis are able to deliver the new natural product lead molecules. Plant-derived anticancer agents in either late preclinical development or early clinical trials include taxol, vincristine, vinblastine, topotecan, irinotecan, etoposide, paclitaxel, and docetaxel. Similarly, anti-cancer agents from microbial sources include dactinomycin, bleomycin, mitomycin C, and doxorubicin. In this review, we highlighted the importance of natural products leads in the discovery and development of novel anti-cancer agents. The semisynthetic modifications of the parent lead to the new anti-cancer agent are also presented. Further, the leads in the preclinical settings with the potential to become effective anticancer agents are also reviewed.Communicated by Ramaswamy H. Sarma.
PubMed: 36255181
DOI: 10.1080/07391102.2022.2134212 -
Caspian Journal of Internal Medicine 2023Low-risk gestational trophoblastic neoplasia could be cured in the case of appropriate management with single-agent chemotherapy. This study was carried out to compare...
BACKGROUND
Low-risk gestational trophoblastic neoplasia could be cured in the case of appropriate management with single-agent chemotherapy. This study was carried out to compare the efficacy of single-dose methotrexate versus Actinomycin-D in low-risk gestational trophoblastic neoplasia to analyze the most effective agent.
METHODS
This retrospective cohort study was conducted on the medical record of 170 cases with the diagnosis of low-risk gestational trophoblastic neoplasia from 2012 to 2019 to evaluate the response rate of single-dose weekly-methotrexate versus biweekly-Actinomycin-D.
RESULTS
Single agent chemotherapy was required in 170 patients with final risk score of less than 7. Among the 100 cases under weekly-methotrexate therapy, 29 patients were required second-line chemotherapy with Actinomycin-D and combination therapy which means complete remission of 71% with methotrexate, in comparison with 78.5% in the other group. Resistance was mostly seen in patients with documented choriocarcinoma in histology who had not received timely diagnosis and treatment.
CONCLUSION
Individualized decision in the management of low-risk gestational trophoblastic neoplasia cases, based on histology, HCG, and history is the corn stone in successful treatment.
PubMed: 36741498
DOI: 10.22088/cjim.14.1.108 -
European Journal of Cancer (Oxford,... Mar 2022Cancer in neonates and infants is a rare but challenging entity. Treatment is complicated by marked physiological changes during the first year of life, excess rates of... (Review)
Review
Cancer in neonates and infants is a rare but challenging entity. Treatment is complicated by marked physiological changes during the first year of life, excess rates of toxicity, mortality, and late effects. Dose optimisation of chemotherapeutics may be an important step to improving outcomes. Body size-based dosing is used for most anticancer drugs used in infants. However, dose regimens are generally not evidence based, and dosing strategies are frequently inconsistent between tumour types and treatment protocols. In this review, we collate available pharmacological evidence supporting dosing regimens in infants for a wide range of cytotoxic drugs. A systematic review was conducted, and available data ranked by a level of evidence (1-5) and a grade of recommendation (A-D) provided on a consensus basis, with recommended dosing approaches indicated as appropriate. For 9 of 29 drugs (busulfan, carboplatin, cyclophosphamide, daunorubicin, etoposide, fludarabine, isotretinoin, melphalan and vincristine), grade A was scored, indicating sufficient pharmacological evidence to recommend a dosing algorithm for infants. For busulfan and carboplatin, sufficient data were available to recommend therapeutic drug monitoring in infants. For eight drugs (actinomycin D, blinatumomab, dinutuximab, doxorubicin, mercaptopurine, pegaspargase, thioguanine and topotecan), some pharmacological evidence was available to guide dosing (graded as B). For the remaining drugs, including commonly used agents such as cisplatin, cytarabine, ifosfamide, and methotrexate, pharmacological evidence for dosing in infants was limited or non-existent: grades C and D were scored for 10 and 2 drugs, respectively. The review provides clinically relevant evidence-based dosing guidance for cytotoxic drugs in neonates and infants.
Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Carboplatin; Etoposide; Humans; Infant; Infant, Newborn
PubMed: 34865945
DOI: 10.1016/j.ejca.2021.11.001 -
Journal of Clinical Oncology : Official... Nov 2022Outcome for patients with metastatic rhabdomyosarcoma (RMS) is poor. This study presents the results of the MTS 2008 study with a pooled analysis including patients from... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Outcome for patients with metastatic rhabdomyosarcoma (RMS) is poor. This study presents the results of the MTS 2008 study with a pooled analysis including patients from the concurrent BERNIE study.
PATIENTS AND METHODS
In MTS 2008, patients with metastatic RMS received four cycles of ifosfamide, vincristine, and actinomycin D (IVA) plus doxorubicin, five cycles of IVA, and 12 cycles of maintenance chemotherapy (low-dose cyclophosphamide and vinorelbine). The BERNIE study randomly assigned patients to the addition or not of bevacizumab to the same chemotherapy. Local therapy (surgery/radiotherapy) was given to the primary tumor and all metastatic sites when feasible.
RESULTS
MTS 2008 included 270 patients (median age, 9.6 years; range, 0.07-20.8 years). With a median follow-up of 50.3 months, 3-year event-free survival (EFS) and overall survival (OS) were 34.9% (95% CI, 29.1 to 40.8) and 47.9% (95% CI, 41.6 to 53.9), respectively. In pooled analyses on 372 patients with a median follow-up of 55.2 months, 3-year EFS and OS were 35.5% (95% CI, 30.4 to 40.6) and 49.3% (95% CI, 43.9 to 54.5), respectively. Patients with ≤ 2 Oberlin risk factors (ORFs) had better outcome than those with ≥ 3 ORFs: 3-year EFS was 46.1% versus 12.5% ( < .0001) and 3-year OS 60.0% versus 26.0% ( < .0001). Induction chemotherapy and maintenance appeared tolerable; however, about two third of patients needed dose adjustments during maintenance.
CONCLUSION
Outcome remains poor for patients with metastatic RMS and multiple ORFs. Because of the design of the studies, it was not possible to determine whether the intensive induction regimen and/or the addition of maintenance treatment resulted in apparent improvement of outcome compared with historical cohorts. Further studies, with novel treatment approaches are urgently needed, to improve outcome for the group of patients with adverse prognostic factors.
Topics: Child; Humans; Disease-Free Survival; Antineoplastic Combined Chemotherapy Protocols; Rhabdomyosarcoma; Sarcoma; Ifosfamide; Vincristine; Cyclophosphamide; Dactinomycin; Doxorubicin; Neoplasms, Second Primary
PubMed: 35709412
DOI: 10.1200/JCO.21.02981 -
SAGE Open Medical Case Reports 2022The Wilms tumour is the fourth most common paediatric malignancy. On the contrary, it is extremely rare in adults as it accounts for less than 1% of all renal...
The Wilms tumour is the fourth most common paediatric malignancy. On the contrary, it is extremely rare in adults as it accounts for less than 1% of all renal malignancies. This scarcity of cases placed a significant challenge in generating evidence-based treatment. Hence, treatment of adult Wilms considerably varies between centres. Standardised guidelines based on international expert consensus for adults have been introduced to help steer management. However, reporting patient outcomes remains limited. In this article, a case study will be presented. This includes modalities of treatment, side effects, tolerability, and outcome. A 40-year-old gentleman with histology consistent with the Wilms tumour received adjuvant chemotherapy according to the UMBRELLA SIOP2016 adult guidelines. Such guidelines were originally adapted from the International Society of Paediatric Oncology protocol. The patient underwent eight cycles of vincristine, actinomycin-D, and doxorubicin and concurrent radiation therapy. Use of the UMBRELLA SIOP2016 adult guideline was shown effective at treating the Wilms tumour in this adult case with minimal severe toxicity. Ongoing follow-up is still needed to determine the long-term effects and prognosis of the patient.
PubMed: 35573098
DOI: 10.1177/2050313X221097265 -
Minerva Medica Feb 2022The aim of this study was to investigate the effect of circular RNA circ ACAP2 on apoptotic phenotype of rat cardiomyocytes and its molecular mechanism.
BACKGROUND
The aim of this study was to investigate the effect of circular RNA circ ACAP2 on apoptotic phenotype of rat cardiomyocytes and its molecular mechanism.
METHODS
Left anterior descending ligation was used to establish a rat myocardial infarction (MI) model, and real-time quantitative polymerase chain reaction (RT-qPCR) was used to detect the expression of circ ACAP2 in apoptotic rat cardiomyocytes. The stability of circ ACAP2 was tested by actinomycin D and RNase R. H9C2 cells were infected by recombinant circ ACAP2 adenovirus (rAd-circ ACAP2), and the expression of apoptotic related genes Bax and BCL-2 in H9C2 was detected. Double luciferase reporter gene experiment, RNA antisense purification experiment and RNA Pull-Down experiments verified the binding effect of circ ACAP2 and miR-29.
RESULTS
RT-qPCR results showed that the expression of circ ACAP2 was increased in cardiomyocytes of MI rats. Actinomycin D and RNase R experiment confirmed that circ ACAP2 had better stability and resistance to RNase R degradation than its host gene ACAP2 mRNA. Overexpression of circ ACAP2 promotes apoptosis. The double luciferase reporter gene assay, RNA antisense purification assay and RNA Pulldown assay consistently confirmed the specific binding effect between circ ACAP2 and miR-29, and circ ACAP2 promoted the apoptotic phenotype in rats.
CONCLUSIONS
The expression of circ ACAP2 increased in cardiomyocytes after MI and promoted apoptosis by binding to miR-29.
Topics: Animals; Apoptosis; GTPase-Activating Proteins; Humans; MicroRNAs; Myocardial Infarction; Myocardium; RNA, Circular; Rats
PubMed: 32406223
DOI: 10.23736/S0026-4806.20.06600-8 -
METTL3 Mediated MALAT1 m6A Modification Promotes Proliferation and Metastasis in Osteosarcoma Cells.Molecular Biotechnology Oct 2023As one of the most ubiquitous types of posttranscriptional modification, N6-methyladenosine (m6A) is extensively implicated in almost all types of cancers, including...
BACKGROUND
As one of the most ubiquitous types of posttranscriptional modification, N6-methyladenosine (m6A) is extensively implicated in almost all types of cancers, including osteosarcoma. Our previous research partially uncovered the role of Metastasis Associated Lung Adenocarcinoma Transcript 1 (MALAT1) in osteosarcoma. However, the relationships between methyltransferase-like 3 (METTL3) and noncoding RNAs modified by METTL3, especially MALAT1, in osteosarcoma remain obscure.
METHODS
The expression of METTL3 in osteosarcoma was evaluated by online bioinformatics analysis, immunohistochemical (IHC) staining, western blotting (WB), and reverse transcription-quantitative PCR (RT‒qPCR). Cell Counting Kit 8 (CCK-8) and Transwell assays were used to evaluate the cell proliferation and invasion abilities. The expression of MALAT1 in osteosarcoma was evaluated by online bioinformatics analysis and RT‒qPCR analysis. m6A methylated RNA immunoprecipitation-qPCR (MeRIP-qPCR) was used to detect m6A modification changes in MALAT1. An actinomycin D assay was used to study changes in the stability of MALAT1.
RESULTS
METTL3 was upregulated in osteosarcoma tissues and cell lines. Functionally, METTL3 promoted the proliferation and migration of osteosarcoma cells. Moreover, a clear positive correlation was found between METTL3 and MALAT1 expression, and MALAT1 was upregulated in osteosarcoma tissues and cells. Mechanistically, the presence of m6A modification sites in MALAT1 and METTL3-mediated m6A modification increased the stability of MALAT1 in osteosarcoma cells and promoted their proliferation and migration.
CONCLUSION
In this study, it was concluded that in osteosarcoma cells, METTL3, acting as an oncogene, promoted m6A modification of MALAT1, increased the stability of MALAT, and enhanced MALAT1-mediated oncogenic function.
PubMed: 37897586
DOI: 10.1007/s12033-023-00953-2 -
Applied Microbiology and Biotechnology Aug 2022Recent years have seen an increased focus on the advancement of naturally derived products for the treatment of cancer. Since the beginning of recorded history, nature... (Review)
Review
Recent years have seen an increased focus on the advancement of naturally derived products for the treatment of cancer. Since the beginning of recorded history, nature has provided a variety of medicinal agents, and an overwhelming number of drugs that we have today are derived from natural sources. Such natural agents are prominently used to treat several diseases such as diabetes, malaria, Alzheimer's, pulmonary disorders, etc. with cancer being the highlight of this review. Due to the rapid development of resistance to chemotherapeutic drugs, the hunt for effective novel drugs is still a paramount concern in cancer treatment. Moreover, many chemotherapy drugs typically have high toxicity and adverse side effects, which necessitates the need to develop anti-tumor drugs that can be employed to treat deadly tumors with fewer negative effects on health and better efficacy. Isolation of several chemotherapeutic drugs has been conducted from a wide range of natural sources which include plants, microbes, fungi, and marine microorganisms. Considering the trends of previous decades, microbial diversity has grown to play a significant role in the formulation of pharmaceuticals and drugs, especially antibiotics and anti-cancer medications. Microbe-derived antitumor antibiotics such as anthracycline, epothilones, bleomycin, actinomycin, and staurosporine are amongst the widely used cancer chemotherapeutic agents. This review deals majorly with microbe-derived anticancer drugs taking into account their derivatives, mechanism of action, isolation procedures, limitations, and tumors targeted by them. This article also reports the phase of clinical study these drugs are undergoing. Moreover, it intends to portray the indispensable part that these microbes have been playing since time immemorial in the odyssey of chemotherapeutic agents. KEY POINTS: • Microbial diversity contributes heavily towards the formulation of anticancer drugs. • Polypeptides, carbohydrates, and alkaloids are prevalent microbe-based drug classes. • Microbe-derived anticancer agents target various sarcomas, carcinomas, and lymphomas.
Topics: Anti-Bacterial Agents; Antineoplastic Agents; Biological Products; Humans; Neoplasms
PubMed: 35819512
DOI: 10.1007/s00253-022-12046-2 -
The Oncologist Dec 20215-fluorouracil-based multiagent chemotherapy has been used as the primary treatment for high-risk gestational trophoblastic neoplasia (GTN) in China for a few decades....
Results with Floxuridine, Actinomycin D, Etoposide, and Vincristine in Gestational Trophoblastic Neoplasias with International Federation of Gynecology and Obstetrics Scores ≥5.
BACKGROUND
5-fluorouracil-based multiagent chemotherapy has been used as the primary treatment for high-risk gestational trophoblastic neoplasia (GTN) in China for a few decades. This study aims to assess the efficacy and toxicity of floxuridine, actinomycin D, etoposide, and vincristine (FAEV) as a primary treatment for patients with GTN who had International Federation of Gynecology and Obstetrics (FIGO) scores ≥5.
MATERIALS AND METHODS
A total of 207 patients with GTN who had FIGO scores ≥5 were treated with FAEV as first-line chemotherapy at Peking Union Medical College Hospital between January 2002 and December 2017. Complete remission (CR), resistance, survival, toxicity, and reproductive outcomes were analyzed.
RESULTS
Of the 207 patients treated with FAEV, 9 (4.3%) required a change of chemotherapy owing to toxicity and 1 (0.5%) died of cerebral hernia 5 weeks after commencing treatment. The remaining 197 patients were assessable to determine the response to FAEV; among them, 168 (85.3%) achieved CR with FAEV and 29 (14.7%) developed resistance to FAEV. The 5-year overall survival rate of the entire cohort was 97.4%. Grade 3-4 neutropenia, thrombocytopenia, and anemia occurred in 28.4%, 6.8%, and 6.2% of cycles, respectively. No acute toxicity-related deaths occurred. Five patients developed acute myeloid leukemia 10-50 months after exposure to chemotherapy; another patient developed duodenal cancer 2 years after completing therapy. Sixty-one patients who preserved fertility wanted to become pregnant; 56 of them conceived.
CONCLUSION
The FAEV regimen is an effective primary treatment for patients with GTN who have FIGO scores ≥5 and has predictable and manageable toxicity.
IMPLICATIONS FOR PRACTICE
The most commonly used multiagent chemotherapy for high-risk gestational trophoblastic neoplasia (GTN) is etoposide, methotrexate and actinomycin D/cyclophosphamide and vincristine (EMA/CO) worldwide. However, 5-fluorouracil-based multiagent chemotherapy has been used as a primary treatment for high-risk GTN in China for a few decades. This study evaluated the efficacy and toxicity of floxuridine, actinomycin D, etoposide, and vincristine (FAEV) as a primary treatment for patients with GTN who have International Federation of Gynecology and Obstetrics (FIGO) scores ≥5. The study's data demonstrated that FAEV as a primary treatment achieved favorable outcomes for patients with FIGO scores ≥5. Toxicities that result from the FAEV regimen are predictable and manageable. The FAEV regimen may provide another option for the treatment of GTN.
Topics: Dactinomycin; Etoposide; Female; Floxuridine; Gestational Trophoblastic Disease; Humans; Obstetrics; Pregnancy; Vincristine
PubMed: 34396643
DOI: 10.1002/onco.13943 -
Cellular Signalling Nov 2023The long non-coding RNA (lncRNA) AGAP2-AS1 was implicated in tumorigenesis, yet with unclear mechanism in the development of Bladder Cancer (BCa).
BACKGROUND
The long non-coding RNA (lncRNA) AGAP2-AS1 was implicated in tumorigenesis, yet with unclear mechanism in the development of Bladder Cancer (BCa).
METHODS
We collected the clinicopathological features and tissue samples of 45 patients with BCa in Xiangya Hospital. Expressions of AGAP2-AS1 and LRG1 were detected by RT-qPCR in BCa tissues and normal tissues as well as in BCa cells. The roles of AGAP2-AS1 and LRG1 were investigated by CCK-8, colony formation assay, transwell assays and tube formation assay. The subcellular localization of AGAP2-AS1 was detected by Fluorescence in situ hybridization. Bioinformatics method, RNA immunoprecipitation, RNA pull-down assay and Actinomycin D test were used to predict and identify the relationships between AGAP2-AS1, LRG1 and IGF2BP2. Xenografted tumors were produced to explore the function of AGAP2-AS1 in BCa in vivo.
RESULTS
AGAP2-AS1 and LRG1 were highly upregulated in BCa. AGAP2-AS1 positively correlated with T stage, grade and vascular invasion, but negatively correlated with the survival of patients. Overexpressions of AGAP2-AS1 promoted proliferation, migration, invasion, tumor angiogenesis in vitro and tumor growth, metastasis in vivo, knockdown of AGAP2-AS1 exhibited the opposite effects. AGAP2-AS1 localized mainly in the cytoplasm. AGAP2-AS1 directly bound to IGF2BP2 protein to enhance LRG1 mRNA stability. Inhibition of BCa progression by AGAP2-AS1 knockdown may be reversed by LRG1 overexpression.
CONCLUSION
AGAP2-AS1 can promote BCa progression and metastasis by recruiting IGF2BP2 to stabilize LRG1.
PubMed: 37541640
DOI: 10.1016/j.cellsig.2023.110839