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MAbs 2019Antibody-drug conjugates (ADCs) that exploit the active metabolite SN-38, which is derived from the popular anticancer drug, irinotecan (a camptothecin that inhibits the... (Review)
Review
Antibody-drug conjugates (ADCs) that exploit the active metabolite SN-38, which is derived from the popular anticancer drug, irinotecan (a camptothecin that inhibits the nuclear topoisomerase I enzyme, inducing double-stranded DNA breaks during the mitotic S-phase of affected cells), represent a substantial advance in the ADC field. SN-38 has been conjugated to a humanized antibody against trophoblast cell surface antigen 2 (TROP-2), which is involved in cancer signaling pathways and has increased expression by many cancer cell types, yielding the ADC sacituzumab govitecan. By conjugating a higher number of SN-38 molecules to the immunoglobulin (drug-to-antibody ratio = 7-8:1), and giving higher (10 mg/kg) and repeated therapy cycles (Days 1 and 8 of 21-day cycles), enhanced drug uptake by the targeted cancer cells is achieved. Based on a unique conjugation method, the lactone ring of the SN-38 molecule is stabilized and the molecule is protected from glucuronidation, a process that contributes to the untoward late diarrhea experienced with irinotecan. Finally, while the ADC is internalized, the use of a moderately stable linker permits release of SN-38 in an acidic environment of the tumor cell and its microenvironment, contributing to a bystander effect on neighboring cancer cells. Here, we discuss the development of sacituzumab govitecan and clinical results obtained using it for the management of patients with advanced, refractive breast, lung, and urinary bladder cancers. Sacituzumab govitecan, which is undergoing accelerated approval review by the US Food and Drug Administration while also being studied in Phase 3 clinical studies, was granted Breakthrough Therapy status from the FDA for advanced, refractory, metastatic triple-negative breast cancer patients.
Topics: Antibodies, Monoclonal, Humanized; Antigens, Neoplasm; Camptothecin; Cell Adhesion Molecules; Clinical Trials, Phase III as Topic; Drug Delivery Systems; Female; Humans; Immunoconjugates; Irinotecan; Male; Neoplasm Proteins; Neoplasms; Tumor Microenvironment
PubMed: 31208270
DOI: 10.1080/19420862.2019.1632115 -
Scientific Reports May 2021Endophytic fungi with the ability to produce plant based secondary metabolites are a potential alternative for producing the host plant metabolite and to prevent natural...
Endophytic fungi with the ability to produce plant based secondary metabolites are a potential alternative for producing the host plant metabolite and to prevent natural plants from extinction. To isolate a high metabolite yielding endophytic strain from plants, hundreds of endophytic strains are screened and tested for product yield separately under axenic state, before shortlisting the potential endophyte, which involves huge time consumption. In this study, strategies for screening and selection of high camptothecin yielding endophytes from their natural habitat were proposed. A correlation was built between the camptothecin yield in the explants and the endophytes isolated from them. In addition, camptothecin yield was compared between the endophytes isolated from young and matured plants. Further, camptothecin producers and non-producers strains were compared for their tolerance toward camptothecin. The study indicates that high camptothecin yielding endophytes were isolated from high yielding explants and younger plants and they were more tolerant to camptothecin in comparison to non-camptothecin yielding endophytes. Thus, choosing a young and high yielding explant for endophyte isolation, and use of camptothecin as a selective agent in the growth medium, can be instrumental in screening and selection of high camptothecin yielding endophytes from nature in relatively less time.
Topics: Camptothecin; Endophytes; Magnoliopsida
PubMed: 34045605
DOI: 10.1038/s41598-021-90778-3 -
Molecules (Basel, Switzerland) May 2022Exploring the metabolic potency of fungi as camptothecin producers raises the hope of their usage as an industrial source of camptothecin, due to their short-life span...
Production, Bioprocessing and Anti-Proliferative Activity of Camptothecin from , "An Endozoic of Marine Sponge, sp.", as a Metabolically Stable Camptothecin Producing Isolate.
Exploring the metabolic potency of fungi as camptothecin producers raises the hope of their usage as an industrial source of camptothecin, due to their short-life span and the feasibility of metabolic engineering. However, the tiny yield and loss of camptothecin productivity of fungi during storage and sub-culturing are challenges that counteract this approach. Marine fungi could be a novel source for camptothecin production, with higher yield and reliable metabolic sustainability. The marine fungal isolate EFBL # OL597937.1 derived from the sponge " sp." has been morphologically identified and molecularly confirmed, based on the Internal Transcribed Spacer sequence, exhibiting the highest yield of camptothecin (110 μg/L). The molecular structure and chemical identity of derived camptothecin has been resolved by HPLC, FTIR and LC-MS/MS analyses, giving the same spectroscopic profiles and mass fragmentation patterns as authentic camptothecin. The extracted camptothecin displayed a strong anti-proliferative activity towards HEP-2 and HCT-116 (IC values 0.33-0.35 µM). The yield of camptothecin was maximized by nutritional optimization of with a Plackett-Burman design, and the productivity of camptothecin increased by 1.8 fold (200 µg/L), compared to control fungal cultures. Upon storage at 4 °C as slope culture for 8 months, the productivity of camptothecin for was reduced by 40% compared to the initial culture. Visual fading of the mycelial pigmentation of was observed during fungal storage, matched with loss of camptothecin productivity. Methylene chloride extracts of sp. had the potency to completely restore the camptothecin productivity of , ensuring the partial dependence of the expression of the camptothecin biosynthetic machinery of on the chemical signals derived from the sponge, or the associated microbial flora. This is the first report describing the feasibility of , endozoic of sp., for camptothecin production, along with reliable metabolic biosynthetic stability, which could be a new platform for scaling-up camptothecin production.
Topics: Animals; Camptothecin; Chromatography, Liquid; Penicillium chrysogenum; Porifera; Tandem Mass Spectrometry
PubMed: 35566384
DOI: 10.3390/molecules27093033 -
Molecular Cancer Therapeutics May 2024In recent years, the field of antibody drug conjugates (ADC) has seen a resurgence, largely driven by the clinical benefit observed in patients treated with ADCs...
In recent years, the field of antibody drug conjugates (ADC) has seen a resurgence, largely driven by the clinical benefit observed in patients treated with ADCs incorporating camptothecin-based topoisomerase I inhibitor payloads. Herein, we present the development of a novel camptothecin ZD06519 (FD1), which has been specifically designed for its application as an ADC payload. A panel of camptothecin analogs with different substituents at the C-7 and C-10 positions of the camptothecin core was prepared and tested in vitro. Selected compounds spanning a range of potency and hydrophilicity were elaborated into drug-linkers, conjugated to trastuzumab, and evaluated in vitro and in vivo. ZD06519 was selected on the basis of its favorable properties as a free molecule and as an antibody conjugate, which include moderate free payload potency (∼1 nmol/L), low hydrophobicity, strong bystander activity, robust plasma stability, and high-monomeric ADC content. When conjugated to different antibodies using a clinically validated MC-GGFG-based linker, ZD06519 demonstrated impressive efficacy in multiple cell line-derived xenograft models and noteworthy tolerability in healthy mice, rats, and non-human primates.
Topics: Camptothecin; Immunoconjugates; Animals; Humans; Mice; Xenograft Model Antitumor Assays; Cell Line, Tumor; Drug Design; Female; Rats
PubMed: 38354417
DOI: 10.1158/1535-7163.MCT-23-0822 -
Frontiers in Cellular and Infection... 2021Irinotecan (CPT11) and its active metabolite ethyl-10-hydroxy-camptothecin (SN38) are broad-spectrum cytotoxic anticancer agents. Both cause cell death in rapidly... (Review)
Review
Irinotecan (CPT11) and its active metabolite ethyl-10-hydroxy-camptothecin (SN38) are broad-spectrum cytotoxic anticancer agents. Both cause cell death in rapidly dividing cells (e.g., cancer cells, epithelial cells, hematopoietic cells) and commensal bacteria. Therefore, CPT11 can induce a series of toxic side-effects, of which the most conspicuous is gastrointestinal toxicity (nausea, vomiting, diarrhea). Studies have shown that the gut microbiota modulates the host response to chemotherapeutic drugs. Targeting the gut microbiota influences the efficacy and toxicity of CPT11 chemotherapy through three key mechanisms: microbial ecocline, catalysis of microbial enzymes, and immunoregulation. This review summarizes and explores how the gut microbiota participates in CPT11 metabolism and mediates host immune dynamics to affect the toxicity and efficacy of CPT11 chemotherapy, thus introducing a new concept that is called "microbiota-host-irinotecan axis". Also, we emphasize the utilization of bacterial β-glucuronidase-specific inhibitor, dietary interventions, probiotics and strain-engineered interventions as emergent microbiota-targeting strategies for the purpose of improving CPT11 chemotherapy efficiency and alleviating toxicity.
Topics: Antineoplastic Agents; Camptothecin; Enzyme Inhibitors; Gastrointestinal Microbiome; Irinotecan
PubMed: 34722328
DOI: 10.3389/fcimb.2021.710945 -
Pharmacogenomics Jul 2010Irinotecan is a camptothecin analog used as an anticancer drug. Severe, potentially life-threatening toxicities can occur from irinotecan treatment. Although multiple... (Review)
Review
Irinotecan is a camptothecin analog used as an anticancer drug. Severe, potentially life-threatening toxicities can occur from irinotecan treatment. Although multiple genes may play a role in irinotecan activity, the majority of evidence to date suggests that variation in expression of UGT1A1 caused by a common promoter polymorphism (UGT1A1*28) is strongly associated with toxicity; however, this link is dose dependent. Variations in other pharmacokinetic genes, particularly the transporter ABCC2, also contribute to irinotecan toxicity. In addition, recent studies have shown that pharmacodynamic genes such as TDP1 and XRCC1 can also play a role in both toxicity and response.
Topics: Antineoplastic Agents, Phytogenic; Camptothecin; Dose-Response Relationship, Drug; Forecasting; Glucuronosyltransferase; Humans; Irinotecan; Multidrug Resistance-Associated Protein 2; Pharmacogenetics; Polymorphism, Genetic
PubMed: 20602618
DOI: 10.2217/pgs.10.95 -
In Vivo (Athens, Greece) 2005Efforts continue to be made in the field of oncology to find new and effective chemotherapeutic agents against cancer. From these efforts the camptothecins have emerged... (Review)
Review
Efforts continue to be made in the field of oncology to find new and effective chemotherapeutic agents against cancer. From these efforts the camptothecins have emerged as a promising group of agents. Camptothecin, first discovered in 1958, was found to be an effective anti-chemotherapeutic agent, but the toxicities were too great to be used in a clinical setting. Derivatives of the original camptothecin molecule have been created by modifying one or more rings in an effort to improve the pharmacokinetics and toxicity profiles of the parent compound. This article reviews both the in vivo and in vitro characteristics of these novel agents.
Topics: Animals; Antineoplastic Agents, Phytogenic; Camptothecin; Clinical Trials as Topic; Drug Evaluation, Preclinical; Drug Screening Assays, Antitumor; Humans; Neoplasms
PubMed: 15796188
DOI: No ID Found -
Annals of Oncology : Official Journal... Sep 1997This review presents a summary of preclinical and clinical data on the topoisomerase I (topo I) inhibitors that are under clinical development. To date, all of the topo... (Review)
Review
This review presents a summary of preclinical and clinical data on the topoisomerase I (topo I) inhibitors that are under clinical development. To date, all of the topo I inhibitors that have been clinically evaluated are analogues of camptothecin, an extract of the Chinese tree Camptotheca acuminata. The therapeutic development of camptothecin was initially limited by its poor solubility and unpredictable toxicity. More recently, a number of water-soluble camptothecin analogues have undergone extensive evaluation and have demonstrated significant clinical activity. These include irinotecan (CPT-II), topotecan, and 9-aminocamptothecin (9-AC). Preliminary data are also reviewed on other camptothecin analogues (GG-211 and DX-8951f), on oral formulations, and on non-camptothecin topoisomerase I inhibitors. The topoisomerase I inhibitors have already demonstrated a broad spectrum of antitumour activity, most probably due to their unique mechanism of action and lack of clinical cross-resistance with existing antineoplastic compounds. The challenge for the next five years is to identify ways to integrate the topo I inhibitors into multidrug and multimodality therapies to achieve optimal antitumour effect, while keeping the side effects of these therapies manageable.
Topics: Animals; Antineoplastic Agents; Camptothecin; Clinical Trials as Topic; Drug Resistance, Neoplasm; Enzyme Inhibitors; Humans; Irinotecan; Topoisomerase I Inhibitors; Topotecan
PubMed: 9358934
DOI: 10.1023/a:1008270717294 -
Molecular Cancer Therapeutics Aug 2018Contrary to other anticancer targets, topoisomerase I (TOP1) is targeted by only one chemical class of FDA-approved drugs: topotecan and irinotecan, the derivatives of...
Contrary to other anticancer targets, topoisomerase I (TOP1) is targeted by only one chemical class of FDA-approved drugs: topotecan and irinotecan, the derivatives of the plant alkaloid, camptothecin. The indenoisoquinolines LMP400, LMP744, and LMP776 are novel noncamptothecin TOP1 inhibitors in clinical trial, which overcome the limitations of camptothecins. To further improve metabolic stability, their methoxy groups have been replaced by fluorine, as in the fluoroindenoisoquinolines NSC 781517 (LMP517), NSC 779135 (LMP135), and NSC 779134 (LMP134). We tested the induction and stability of TOP1 cleavage complexes (TOP1cc), and the induction and persistence of DNA damage measured by histone H2AX phosphorylation (γH2AX) compared with their parent compounds LMP744 and LMP776 in leukemia CCRF-CEM and colon carcinoma HCT116 cells. The fluoroindenoisoquinolines induced TOP1cc and γH2AX at nanomolar concentrations, and at higher levels than the parent indenoisoquinolines. The fluoroindenoisoquinoline LMP135 showed greater antitumor activity than topotecan in small-cell lung cancer cell H82 xenografts. It was also more potent than topotecan in the NCI-60 cancer cell line panel. Bioinformatics tools (http://discover.nci.nih.gov/cellminercdb) were used to investigate the following: (i) the correlations of fluoroindenoisoquinolines activity with other drugs, and (ii) genomic determinants of response in the NCI-60. The activity of the fluoroindenoisoquinolines was mostly correlated with camptothecin derivatives and the parent indenoisoquinolines, consistent with TOP1 targeting. Genomic analyses and activity assays in CCRF-CEM -deleted cells showed that expression is a dominant determinant of response to LMP135. This study shows the potential value of the fluoroindenoisoquinolines for further development as novel anticancer agents targeting TOP1. .
Topics: Animals; Camptothecin; Female; Humans; Mice; Mice, Nude; Topoisomerase I Inhibitors
PubMed: 29748210
DOI: 10.1158/1535-7163.MCT-18-0028 -
Medicinal Research Reviews Jul 2015Camptothecins (CPTs) are cytotoxic natural alkaloids that specifically target DNA topoisomerase I. Research on CPTs has undergone a significant evolution from the... (Review)
Review
Camptothecins (CPTs) are cytotoxic natural alkaloids that specifically target DNA topoisomerase I. Research on CPTs has undergone a significant evolution from the initial discovery of CPT in the late 1960s through the study of synthetic small-molecule derivatives to investigation of macromolecular constructs and formulations. Over the past years, intensive medicinal chemistry efforts have generated numerous CPT derivatives. Three derivatives, topotecan, irinotecan, and belotecan, are currently prescribed as anticancer drugs, and several related compounds are now in clinical trials. Interest in other biological effects, besides anticancer activity, of CPTs is also growing exponentially, as indicated by the large number of publications on the subject during the last decades. Therefore, the main focus of the present review is to provide an ample but condensed overview on various biological activities of CPT derivatives, in addition to continued up-to-date coverage of anticancer effects.
Topics: Anti-Infective Agents; Antineoplastic Agents; Camptothecin; Humans
PubMed: 25808858
DOI: 10.1002/med.21342