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The management and treatment of cancer and related disorders is still a challenging goal for the scientists. The current global scenario of cancer mortality is demanding to discover and develop new, safe, cost effective and potent anticancer medications. The anticancer drugs vinblastine and vincristine are solely produced by medicinal herb Catharanthus roseus. These drugs are second most widely consumed anticancer drugs after Taxol in the world; however, the plant is well recognised to produce very modest levels of these important compounds (0.0002–0.0005 %). To address this issue, the review delves into the promising alternative of using endophytic fungi which reside within the healthy plant tissues and have ability to produce host-specific bioactive compounds including vinblastine and vincristine. An endophytic fungus Talaromyces radicus is reported to produce vincristine up to 670 µg/L while Curvularia verruculosa is able to secret vinblastine at a concentration of 182 µg/L in liquid cultures respectively. Some other fungal species reported to produce either vincristine or vinblastine includes Fusarium, Alternaria, Chaetomium, Nigrospora and Eutypella. The review begins by discussing the therapeutic importance of vinblastine and vincristine, highlighting their mechanisms of action and their critical roles in chemotherapy regimens for various types of cancer. Next, the review also provides an in-depth analysis of various endophytic fungi producing vinblastine and vincristine detailing their identification, characterization, biosynthetic ability and strain improvement processes. It aims to contribute to the ongoing efforts to develop more effective and sustainable strategies for producing these critical anticancer agents, ultimately enhancing cancer treatment options and outcomes. [Display omitted] • Vinblastine and vincristine are among the major anticancer compounds used worldwide for treatment of various cancers. • Natural production of these anticancer drugs is limited because of the very low yield in Catharanthus plant. • The endophytic fungi isolated from Catharanthus roseus are reported to produce vinblastine and vincristine in sufficient quantities. • The challenge in fungal production of these drugs is related with optimization and sustainable yield at commercial level. [ABSTRACT FROM AUTHOR]

Periwinkle Cathranthus roseus is an ornamental plant that produces over 200 alkaloids, including vincristine, vinblastine, and vindoline, which are used to treat various types of cancer. However, the low yield of terpenoid indole alkaloids (TIAs) from periwinkle and the high cost of extraction has led researchers to explore alternative methods for their production. The study aims to investigate the influence of polyethylene glycol (PEG) as an elicitor to enhance alkaloid production in periwinkle callus cultures while examining the efficacy and safety of using PEG. Callus was induced and abiotic elicitation experiments were conducted to study callus growth enhancement. The dry weight of the callus was calculated, and vincristine, vinblastine and vindoline were extracted and analyzed using high-performance liquid chromatography. The results showed that low to moderate concentrations of PEG4000 can enhance callus growth, while higher concentrations can reduce it. The addition of PEG4000 also increased the production of important alkaloids, including vindoline, vincristine, and vinblastine, by up to 2.65-fold. The findings suggest that PEG4000 can be used to optimize the production of alkaloids in C. roseus callus cultures. [ABSTRACT FROM AUTHOR]

Classical Hodgkin lymphoma (CHL) is characterized by a proliferation of malignant cells of the lymphoreticular system and often involves lymph nodes, spleen, liver, and bone marrow; it is rare in the head and neck region. A 58-year-old man had an enlargement with ulceration in the left palatine tonsil that was causing dysphagia. Microscopic examination revealed an infiltrate of large, atypical lymphoid cells positive for cluster of differentiation 30, cluster of differentiation 15, PAX5, and Epstein-Barr virus. Complementary tests initially ruled out other sites of the disease. The results led to diagnosis of a rare development of CHL in the palatine tonsil, which was staged as IIEB. Before therapy was initiated, nodal lesions developed in the neck and the CHL was restaged as IIB. The patient was treated successfully with a regimen of doxorubicin, bleomycin, vinblastine, and dacarbazine. After a review of the literature, the authors found only 3 cases with the clinical, imaging, and microscopic features of primary CHL of the palatine tonsil. Despite being a rare event, CHL may first develop in extranodal sites, such as the palatine tonsil. In this context, the role of the dentist is pivotal for early diagnosis of the disease. Investigations into the development of primary tonsillar CHL in the oropharynx are needed because the disease has a different clinical course than nodal lesions. [ABSTRACT FROM AUTHOR]

This study investigates the synthesis of vinblastine by endophytic fungi isolated from leaf of C. roseus. A total of 10 endophytic fungi were selected for secretion of vinca alkaloids based on the initial screening by biochemical tests and thin-layer chromatography (TLC). Out of these ten, only four fungal extracts showed positive results for presence of vinblastine at same retention time (10 min.) compared to reference compound on HPLC analysis. The detected concentration of vinblastine was maximum (17 µg/ml) in isolate no. CRL 22 followed by CRL 52, CRL 17 and CRL 28. To validate the presence of vinblastine, ultra-high-performance liquid chromatography coupled with high-resolution accurate mass spectrometry (HRMS) was employed. This analysis confirmed the presence of anhydrovinblastine, a precursor of vinblastine through the detection of molecular ions at m/z 793.4185 in extract of CRL 17. In addition to anhydrovinblastine, the intermediate compounds essential to the biosynthetic pathway of vinblastine were also detected in the extract of CRL 17. These host-origin compounds strongly suggest the presence of a biosynthetic pathway within the endophytic fungus. Based on morphological observation and sequence analysis of the ITS region of rDNA, endophytic fungi were identified as Alternaria alternata (CRL 17), Curvularia lunata (CRL 28), Aspergillus terrus (CRL 52), and Aspergillus clavatonanicus (CRL 22). [ABSTRACT FROM AUTHOR]

Abstract A biotransformation pair consisting of vinblastine: vincristine present in the Catharanthus roseus plant is of immense pharmacological significance. In this study, we successfully transformed vinblastine into vincristine outside the plant using Pseudomonas aeruginosa 8485 and Pseudomonas fluorescens 2421 and evaluated the antiangiogenic potential of thus produced vincristine through the CAM assay. The toxicity assay showed that both Pseudomonas spp. can tolerate varying concentrations (25–100 µl of 1 mg/ml) of vinblastine. The biotransformation was performed in a liquid nutrient broth medium containing vinblastine (25–100 µl), and Pseudomonas spp. inoculums (50–150 µl) by incubating at 30 °C and 37 °C, respectively for 8 days. The process was optimized for substrate and culture concentrations, pH, temperature, and rotation speed (rpm) for the highest conversion. Analysis using LC–MS/MS confirmed the presence of vincristine as a product of the vinblastine biotransformation by two Pseudomonas spp. P. fluorescens 2421 showed a faster conversion rate with 95% of vinblastine transformed within 24 h than P. aeruginosa 8485, which demonstrated a conversion rate of 92% on the 8th day. From LC–MS/MS analysis, the optimal conditions for the reaction were determined as vinblastine (25 µl), microbial inoculums (150 µl or 200 × 106 and 210 × 106 CFU/ml), pH 7.4, rotation speed of 180 rpm, and temperatures of 30 °C and 37 °C with incubation time of 8 days. The vincristine produced exhibited potent antiangiogenic activity in the CAM assay reducing the thickness and branching of blood vessels in a dose-dependent manner. The study concludes that both Pseudomonas spp. showed promise for vincristine production from vinblastine, without compromising its antiangiogenic properties.

Introduction. Microtubules are highly dynamic polymers of α, β-tubulin dimers involves in a broad spectrum of the processes, such as intracellular transport and cell proliferation. This makes them an attractive molecular target for anti-cancer therapies. Substances that affect the dynamic state of tubulin microtubules are known as the mitotic poisons that are effectiveand widely used in the chemotherapy of various tumors. Mitotic poisons are able to interfere with polymerization (stabilization) or depolymerization of tubulin, which in turn leads to the arrest of cells in the M-phase (named as a mitotic catastrophe) and their subsequent death via activation of apoptotic mechanisms. However, the effectiveness of MP-based therapies is gradually decreasing over the time due to development of multiple drug resistance mechanisms in cancer cells. Thus, development of novel compounds selectively targeting tubulin and effectively overcoming multiple drugresistance phenotype in cancer is an urgent need in current oncology. Aim. To examine the cytotoxic and antitumor activities of several pyrrole-containing heterocyclic compounds (EPC-91, EPC-92 and PCA-93) against cancer cell lines with epithelial and mesenchymal origin, including those with multiple drug resistance phenotype. Materials and methods. Studies were performed on parental human cancer cell lines – triple-negative breast cancer HCC1806, gastrointestinal stromal tumor GIST T-1, osteosarcoma SaOS-2, – sensitive to chemotherapy (paclitaxel, doxorubicin) and their resistant sublines (HCC1806 Tx-R, GIST T-1 Tx-R, SaOS-2 Dox-R), as well as on murine colorectal adenocarcinoma cell line Colon-26, exhibiting primary resistance to the aforementioned chemotherapeutic agents. Results. The cytotoxic activities of EPC-91 and PCA-93 were due to their abilities to depolymerize tubulin. The results of immunofluorescence microscopy and Western blotting indicated that the compounds disrupt assembly of tubulin microtubules and prevent polymerization of α-tubulin in cancer cells. Inhibition of tubulin polymerizations led to significant increasein number of round-shaped and phospho-histone 3 (e. g. mitotic) cells, followed by their death through apoptosis. PCA-93 also exhibited potent anti-tumor effect against Colon-26 cells due to its anti-proliferative and proapoptotic activities. Conclusion. The data shown here illustrates potent cytotoxic activities of EPC-91 and PCA-93 against multiple cancer cell lines in vitro including those with multiple drug resistance phenotype. Similarly, PCA-93 was found to be highly effective against Colon-26 cell in vivo, thereby illustrating the attractive platform for the development of novel pyrrole-based agents exhibiting potent anti-tumor activities.

A biotransformation pair consisting of vinblastine: vincristine present in the Catharanthus roseus plant is of immense pharmacological significance. In this study, we successfully transformed vinblastine into vincristine outside the plant using Pseudomonas aeruginosa 8485 and Pseudomonas fluorescens 2421 and evaluated the antiangiogenic potential of thus produced vincristine through the CAM assay. The toxicity assay showed that both Pseudomonas spp. can tolerate varying concentrations (25–100 µl of 1 mg/ml) of vinblastine. The biotransformation was performed in a liquid nutrient broth medium containing vinblastine (25–100 µl), and Pseudomonas spp. inoculums (50–150 µl) by incubating at 30 °C and 37 °C, respectively for 8 days. The process was optimized for substrate and culture concentrations, pH, temperature, and rotation speed (rpm) for the highest conversion. Analysis using LC–MS/MS confirmed the presence of vincristine as a product of the vinblastine biotransformation by two Pseudomonas spp. P. fluorescens 2421 showed a faster conversion rate with 95% of vinblastine transformed within 24 h than P. aeruginosa 8485, which demonstrated a conversion rate of 92% on the 8th day. From LC–MS/MS analysis, the optimal conditions for the reaction were determined as vinblastine (25 µl), microbial inoculums (150 µl or 200 × 106 and 210 × 106 CFU/ml), pH 7.4, rotation speed of 180 rpm, and temperatures of 30 °C and 37 °C with incubation time of 8 days. The vincristine produced exhibited potent antiangiogenic activity in the CAM assay reducing the thickness and branching of blood vessels in a dose-dependent manner. The study concludes that both Pseudomonas spp. showed promise for vincristine production from vinblastine, without compromising its antiangiogenic properties. [ABSTRACT FROM AUTHOR]

Simple Summary: Three-dimensional (3D) telomere analysis using TeloView v 2.2 has shown promise in quantifying genomic instability and predicting therapy response. In a study of 156 Classic Hodgkin's lymphoma (cHL), we identified significant 3D telomere parameters that predict patient outcomes. A predictive model using four 3D telomere parameters, including the proportion of t-stumps (very short telomeres), achieved an area under curve (AUC) of 0.83, with a sensitivity and specificity of 0.82 and 0.78, respectively. Classic Hodgkin's lymphoma (cHL) is a curable cancer with a disease-free survival rate of over 10 years. Over 80% of diagnosed patients respond favorably to first-line chemotherapy, but few biomarkers exist that can predict the 15–20% of patients who experience refractory or early relapsed disease. To date, the identification of patients who will not respond to first-line therapy based on disease staging and traditional clinical risk factor analysis is still not possible. Three-dimensional (3D) telomere analysis using the TeloView® software platform has been shown to be a reliable tool to quantify genomic instability and to inform on disease progression and patients' response to therapy in several cancers. It also demonstrated telomere dysfunction in cHL elucidating biological mechanisms related to disease progression. Here, we report 3D telomere analysis on a multicenter cohort of 156 cHL patients. We used the cohort data as a training data set and identified significant 3D telomere parameters suitable to predict individual patient outcomes at the point of diagnosis. Multivariate analysis using logistic regression procedures allowed for developing a predictive scoring model using four 3D telomere parameters as predictors, including the proportion of t-stumps (very short telomeres), which has been a prominent predictor for cHL patient outcome in a previously published study using TeloView® analysis. The percentage of t-stumps was by far the most prominent predictor to identify refractory/relapsing (RR) cHL prior to initiation of adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) therapy. The model characteristics include an AUC of 0.83 in ROC analysis and a sensitivity and specificity of 0.82 and 0.78 respectively. [ABSTRACT FROM AUTHOR]

Advancements in cancer treatment have underscored the importance of understanding the intricate interplay between tumour microenvironments and drug delivery mechanisms. This research delves into the dynamic relationship between blood-mediated drug transport and the density of the tumour matrix within solid tumours. The study seeks to unravel the effects of varying tumour matrix densities on drug transport characteristics and, subsequently, on the perfusion efficacy of therapeutic agents. Through computational fluid dynamics simulation, this research elucidates the intricate balance between transport dynamics and drug distribution within solid tumours. A simple two-dimensional circular geometry has been chosen to represent the tumour and the surrounding microcirculation. The drug molecules diffuse into the interstitial tumour matrix through the microcirculation and then from the matrix into the tumour cells. The matrix is considered to be a porous medium, and the porosity of the media has been varied to simulate the effect of the matrix density on drug perfusion. Simulation results have shown that the density significantly affects the transport flux of the drug through the tumour matrix. The outcomes of this research hold potential implications for optimising drug delivery strategies in cancer therapy possibly by designing drug molecules that can effectively diffuse through dense tumour matrices. [ABSTRACT FROM AUTHOR]

Background: Cytotoxic medicine contamination of preparation and administration areas of oncology healthcare facilities poses a risk to staff facing repeated low‐level exposure over time. The use of closed‐system transfer devices (CSTDs) during preparation and administration of cytotoxic products may reduce the levels of contamination. The primary aim was to determine the levels of cytotoxic medicine contamination in preparation and administration areas of hospitals that use CSTDs compared to those that do not. Aim: The primary aim was to determine the levels of cytotoxic medicine contamination in preparation and administration areas of hospitals that use CSTDs compared to those that do not. Method: A retrospective, cross‐sectional study across four Australian hospitals was conducted. Cytotoxic medicine contamination was determined via surface wipe sampling on six specified surfaces. The samples were tested for cyclophosphamide, docetaxel, etoposide, ifosfamide, irinotecan, methotrexate, paclitaxel, pemetrexed, topotecan, and vinblastine. This project was exempt due to the local policy requirements that constitute research by the South Eastern Sydney Local Health District Human Research Ethics Committee (Reference no: ETH01899). The justification for this ethics exemption was as follows: this was a study involving sample testing only and did not include human participants or participation. Results: Environmental contamination with cytotoxic medications was observed at all hospitals, regardless of the CSTD used. Of the 24 samples tested, the agent most frequently seen was ifosfamide with 29% (n = 7), followed by cyclophosphamide 13% (n = 3), and methotrexate 8% (n = 2). There was no statistically significant difference between hospitals that used CSTDs compared to hospitals that did not (25% vs 42%, p = 0.67). Contamination was more extensive in preparation areas than administration areas, and was observed on the biological safety cabinets (BSC) worktop, packaging bench, and floor in front of the BSCs. Conclusion: All sites had contamination present for cytotoxic medicines. There was no statistically significant difference in the proportion of contaminated surfaces between sites that used CSTDs versus sites where CSTDs were not used. Only ifosfamide contamination was identified in pharmacy areas that used CSTDs. Safe work practices and staff training are encouraged to further minimise exposure risk. [ABSTRACT FROM AUTHOR]