Review

Authors: Semir Vranić, Semir Bešlija, Zoran Gatalica...

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

Review

Authors: David M Goldenberg, Robert M Sharkey

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

Review

Authors: Sharon Marsh, Janelle M Hoskins

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

Authors: Abhishek G Sathe, Indrajeet Singh, Pratap Singh...

BACKGROUND AND OBJECTIVE

Sacituzumab govitecan (SG) is an antibody-drug conjugate composed of an antibody with affinity for Trop-2 coupled to SN-38 via hydrolyzable linker. SG is approved for patients with metastatic triple-negative breast cancer (mTNBC) who have received two or more prior chemotherapies (at least one in a metastatic setting) and for patients with pretreated hormone receptor positive (HR+)/human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer.

METHODS

In these analyses, the pharmacokinetics of SG, free SN-38, and total antibody (tAB) were characterized using data from 529 patients with mTNBC or other solid tumors across two large clinical trials (NCT01631552; ASCENT, NCT02574455). Three population pharmacokinetic models were constructed using non-linear mixed-effects modeling; clinically relevant covariates were evaluated to assess their impact on exposure. Models for SG and tAB were developed independently whereas free SN-38 was sequentially generated via a first-order release process from SG.

RESULTS

Pharmacokinetics of the three analytes were each described by a two-compartment model with estimated body weight-based scaling exponents for clearance and volume. Typical parameter estimates for clearance and steady-state volume of distribution were 0.133 L/h and 3.68 L for SG and 0.0164 L/h and 4.26 L for tAB, respectively. Mild-to-moderate renal impairment, mild hepatic impairment, age, sex, baseline albumin level, tumor type, UGT1A1 genotype, or Trop-2 expression did not have a clinically relevant impact on exposure for any of the three analytes.

CONCLUSIONS

These analyses support the approved SG dosing regimen of 10 mg/kg as intravenous infusion on days 1 and 8 of 21-day cycles and did not identify a need for dose adjustment based on evaluated covariates or disease characteristics.

Topics: Adult; Aged; Aged, 80 and over; Female; Humans; Male; Middle Aged; Young Adult; Antibodies, Monoclonal, Humanized; Camptothecin; Immunoconjugates; Irinotecan; Models, Biological; Neoplasm Metastasis; Neoplasms; Triple Negative Breast Neoplasms

PubMed: 38578394
DOI: 10.1007/s40262-024-01366-3

Review

Authors: Pablo Botella, Eva Rivero-Buceta

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

Authors: Barry C Mirtsching, James N George, Richard H Aster...

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Phytogenic; Bevacizumab; Camptothecin; Colonic Neoplasms; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Middle Aged; Platelet Count; Thrombocytopenia

PubMed: 24472819
DOI: 10.1097/MAJ.0000000000000243

Review

Authors: Brittney K Mize, Amrita Salvi, Yulin Ren...

Covering: 2015 through the end of July 2022Ovarian cancer is one of the most common cancers affecting the female reproductive organs and has the highest mortality rate among gynecological cancers. Although botanical drugs and their derivatives, namely members of the taxane and camptothecin families, represent significant therapeutics currently available for the treatment of ovarian cancer, new drugs that have alternative mechanisms of action are still needed to combat the disease. For this reason, many efforts to identify additional novel compounds from botanical sources, along with the further development of existing therapeutics, have continued to appear in the literature. This review is designed to serve as a comprehensive look at both the currently available small-molecule therapeutic options and the recently reported botanically-derived natural products currently being studied and developed as potential future therapeutics that could one day be used against ovarian cancer. Specifically, key properties, structural features, and biological data are highlighted that are important for the successful development of potential agents. Recently reported examples are specifically discussed in the context of "drug discovery attributes," including the presence of structure-activity relationship, mechanism of action, toxicity, and pharmacokinetic studies, to help indicate the potential for future development and to highlight where these compounds currently exist in the development process. The lessons learned from both the successful development of the taxanes and camptothecins, as well as the strategies currently being employed for new drug development, are expected to ultimately help guide the future development of botanical natural products for ovarian cancer.

Topics: Female; Humans; Biological Products; Camptothecin; Ovarian Neoplasms

PubMed: 37387219
DOI: 10.1039/d2np00091a

Authors: Shahrina Alam, Daiane S Alves, Stuart A Whitehead...

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

Review

Authors: J Dancey, E A Eisenhauer

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

Review

Authors: Zhiqiang Cai, Jiyuan Yang, Xiaoyan Shu...

Chemotherapy-associated hepatotoxicity in liver metastatic colorectal cancer is attracting more and more attention for clinicians. This hepatotoxicity heralds an increased risk of morbidity and mortality in patients with colorectal liver metastases, therefore it is important that clinicians have an adequate knowledge of the chemotherapy-associated hepatotoxicity.

Topics: Camptothecin; Chemical and Drug Induced Liver Injury; Colorectal Neoplasms; Fatty Liver; Fluorouracil; Humans; Irinotecan; Non-alcoholic Fatty Liver Disease

PubMed: 24965391
DOI: No ID Found