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Bosnian Journal of Basic Medical... Feb 2021Functional activation of human epidermal growth factor receptor 2 (HER2) has been shown to strongly promote carcinogenesis, leading to the investigation of HER2-directed... (Review)
Review
Functional activation of human epidermal growth factor receptor 2 (HER2) has been shown to strongly promote carcinogenesis, leading to the investigation of HER2-directed agents in cancers with HER2 genomic alterations. This has been best documented in the context of HER2 gene amplification in breast and gastric/gastroesophageal junction carcinomas for which several HER2-directed agents are available and have become a part of standard treatment regimens. Somatic HER2 gene mutations have been recently described at low frequency in a variety of human cancers and have emerged as a novel predictive biomarker for HER2-directed therapies. Preclinical data also indicate that activating HER2 mutations are potent oncogenic drivers in a manner that is analogous to HER2 amplification. HER2 mutations may clinically confer sensitivity to HER2-directed agents as recently shown in a phase II clinical trial with antibody-drug conjugate against HER2 trastuzumab deruxtecan in patients with non-squamous non-small cell lung carcinoma.
Topics: Antibodies, Monoclonal, Humanized; Camptothecin; Carcinogenesis; Humans; Immunoconjugates; Mutation; Neoplasms; Receptor, ErbB-2; Trastuzumab
PubMed: 32530388
DOI: 10.17305/bjbms.2020.4908 -
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 -
Journal of Controlled Release :... Feb 2017Twenty-(S)-camptothecin is a strongly cytotoxic molecule with excellent antitumor activity over a wide spectrum of human cancers. However, the direct formulation is... (Review)
Review
Twenty-(S)-camptothecin is a strongly cytotoxic molecule with excellent antitumor activity over a wide spectrum of human cancers. However, the direct formulation is limited by its poor water solubility, low plasmatic stability and severe toxicity, which currently limits its clinical use. As a consequence, two strategies have been developed in order to achieve safe and efficient delivery of camptothecin to target cells: structural analogues and nanomedicines. In this review, we summarize recent advances in the design, synthesis and development of camptothecin molecular derivatives and supramolecular vehicles, following a systematic classification according to structure-activity relationships (structural analogues) or chemical nature (nanomedicines). A series of organic, inorganic and hybrid materials are presented as nanoplatforms to overcome camptothecin restrictions in administration, biodistribution, pharmacokinetics and toxicity. Nanocarriers which respond to a variety of stimuli endogenously (e.g., pH, redox potential, enzyme activity) or exogenously (e.g., magnetic field, light, temperature, ultrasound) seem the best positioned therapeutic materials for optimal spatial and temporal control over drug release. The main goal of this review is to be used as a source of relevant literature for others interested in the field of camptothecin-based therapeutics. To this end, final remarks on the most important formulations currently under clinical trial are provided.
Topics: Animals; Antineoplastic Agents, Phytogenic; Camptothecin; Clinical Trials as Topic; Delayed-Action Preparations; Drug Delivery Systems; Drug Liberation; Humans; Models, Molecular; Nanomedicine; Nanoparticles; Topoisomerase I Inhibitors
PubMed: 28027948
DOI: 10.1016/j.jconrel.2016.12.023 -
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 -
British Journal of Cancer Aug 1996The camptothecins are a new class of chemotherapeutic agents which have a novel mechanism of action targeting the nuclear enzyme topoisomerase I. Knowledge of the... (Review)
Review
The camptothecins are a new class of chemotherapeutic agents which have a novel mechanism of action targeting the nuclear enzyme topoisomerase I. Knowledge of the structure-activity relationships of the parent compound camptothecin has led to the development of effective soluble analogues with manageable toxicities. Broad anti-tumour activity shown in preclinical studies has been confirmed in phase I/II studies for irinotecan and topotecan. Two other derivatives, 9-aminocamptothecin and GI 147211C, are undergoing phase I and early phase II evaluation. Although camptothecin is a plant extract, it and most of its derivatives are not affected by the classic P-gpMDR1 mechanism of resistance which may allow the development of novel combination chemotherapeutic regimens. Important areas of future endeavour will include the development of rational combination regimens and the pursuit of randomised trials. Based on single agent data, colorectal cancer and non-small-cell lung cancer should be the focus for future irinotecan studies. Small-cell lung cancer and ovarian carcinoma are logical tumour types to pursue with topotecan. Both 9-aminocamptothecin and GI 147211C are too early in their clinical evaluation to make recommendations about their future roles. Finally, the unfolding story of camptothecin analogue development will give important insights into the predictive value of preclinical observations on relative efficacy, schedule dependency, combination strategies and resistance mechanisms which have helped determine the strategies for clinical evaluation of these agents.
Topics: Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Drug Resistance; Humans; Irinotecan; Neoplasms; Topoisomerase I Inhibitors; Topotecan
PubMed: 8695345
DOI: 10.1038/bjc.1996.362 -
Bioconjugate Chemistry Jun 2015For drug delivery purposes, the ability to conveniently attach a targeting moiety that will deliver drugs to cells and then enable controlled release of the active...
For drug delivery purposes, the ability to conveniently attach a targeting moiety that will deliver drugs to cells and then enable controlled release of the active molecule after localization is desirable. Toward this end, we designed and synthesized clickable and photocleavable lipid analogue 1 to maximize the efficiency of bioconjugation and triggered release. This compound contains a dibenzocyclooctyne group for bioorthogonal derivatization linked via a photocleavable 2-nitrobenzyl moiety at the headgroup of a synthetic lipid backbone for targeting to cell membranes. To assess delivery and release using this system, we report fluorescence-based assays for liposomal modification and photocleavage in solution as well as through surface immobilization to demonstrate successful liposome functionalization and photoinduced release. In addition, fluorophore delivery to and release from live cells was confirmed and characterized using fluorescence microscopy and flow cytometry analysis in which 1 was delivered to cells, derivatized, and photocleaved. Finally, drug delivery studies were performed using an azide-tagged analogue of camptothecin, a potent anticancer drug that is challenging to deliver due to poor solubility. In this case, the ester attachment of the azide tag acted as a caging group for release by intracellular esterases rather than through photocleavage. This resulted in a dose-dependent response in the presence of liposomes containing delivery agent 1, confirming the ability of this compound to stimulate delivery to the cytoplasm of cells.
Topics: Antineoplastic Agents, Phytogenic; Azides; Camptothecin; Cell Membrane; Cell Proliferation; Delayed-Action Preparations; Drug Delivery Systems; HeLa Cells; Humans; Light; Lipids; Liposomes; Neoplasms; Optical Imaging; Photochemical Processes; Saccharomyces cerevisiae
PubMed: 25927978
DOI: 10.1021/acs.bioconjchem.5b00044 -
BMC Gastroenterology Apr 2018For patients with advanced gastric cancer (AGC), second-line chemotherapy regimen remains controversial. The efficacy and safety of irinotecan-containing doublet... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
For patients with advanced gastric cancer (AGC), second-line chemotherapy regimen remains controversial. The efficacy and safety of irinotecan-containing doublet treatment and irinotecan monotherapy were compared in this systematic analysis.
METHODS
A search was conducted on EMBASE and Medline databases. All articles compared irinotecan-containing doublet to irinotecan as second-line chemotherapy for AGC. STATA statistical software (Version 12.0) was used to analyze the data.
RESULTS
Seven studies, including 905 cases, were included in the analysis. Irinotecan-containing doublet treatment significantly prolonged progression-free survival compared to irinotecan monotherapy (HR = 0.82, 95% CI: 0.70-0.95). However, doublet treatment neither significantly prolong overall survival compared to monotherapy (HR = 0.94, 95% CI: 0.81-1.10), nor did it significantly increase the overall response rates and disease control rates, when compared to monotherapy. In addition, the irinotecan-containing doublet group had an increase in incidences of ≥ Grade 3 neutropenia (RR = 1.23, 95% CI: 1.01-1.51) and anemia (RR = 2.00, 95% CI: 1.37-2.92).
CONCLUSIONS
When compared to irinotecan monotherapy, irinotecan-containing doublet treatment increased progression free survival and was tolerable as a second- line chemotherapy for AGC.
Topics: Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Disease-Free Survival; Humans; Irinotecan; Stomach Neoplasms; Treatment Outcome
PubMed: 29609559
DOI: 10.1186/s12876-018-0772-4