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1.
Bull Exp Biol Med ; 177(1): 30-34, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38954304

RESUMO

Topotecan administered intraperitoneally at single doses of 0.25, 0.5, and 1 mg/kg induced chromosomal aberrations in bone marrow cells of F1(CBA×C57BL/6) hybrid mice in a dose-dependent manner. A tyrosyl-DNA phosphodiesterase 1 (TDP1) inhibitor, an usnic acid derivative OL9-116 was inactive in a dose range of 20-240 mg/kg, but enhanced the cytogenetic effect of topotecan (0.25 mg/kg) at a dose of 40 mg/kg (per os). The TDP1 inhibitor, a coumarin derivative TX-2552 (at doses of 20, 40, 80, and 160 mg/kg per os), increased the level of aberrant metaphases induced by topotecan (0.25 mg/kg) by 2.1-2.6 times, but was inactive at a dose of 10 mg/kg. The results indicate that TDP1 inhibitors enhance the clastogenic activity of topotecan in mouse bone marrow cells in vivo and are characterized by different dose profiles of the co-mutagenic effects.


Assuntos
Células da Medula Óssea , Diester Fosfórico Hidrolases , Topotecan , Animais , Topotecan/farmacologia , Camundongos , Diester Fosfórico Hidrolases/metabolismo , Células da Medula Óssea/efeitos dos fármacos , Masculino , Aberrações Cromossômicas/efeitos dos fármacos , Aberrações Cromossômicas/induzido quimicamente , Inibidores de Fosfodiesterase/farmacologia , Inibidores da Topoisomerase I/farmacologia , Camundongos Endogâmicos C57BL , Mutagênicos/toxicidade
2.
J Control Release ; 371: 371-385, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38849089

RESUMO

The efficacy of DNA-damaging agents, such as the topoisomerase I inhibitor SN38, is often compromised by the robust DNA repair mechanisms in tumor cells, notably homologous recombination (HR) repair. Addressing this challenge, we introduce a novel nano-strategy utilizing binary tumor-killing mechanisms to enhance the therapeutic impact of DNA damage and mitochondrial dysfunction in cancer treatment. Our approach employs a synergistic drug pair comprising SN38 and the BET inhibitor JQ-1. We synthesized two prodrugs by conjugating linoleic acid (LA) to SN38 and JQ-1 via a cinnamaldehyde thioacetal (CT) bond, facilitating co-delivery. These prodrugs co-assemble into a nanostructure, referred to as SJNP, in an optimal synergistic ratio. SJNP was validated for its efficacy at both the cellular and tissue levels, where it primarily disrupts the transcription factor protein BRD4. This disruption leads to downregulation of BRCA1 and RAD51, impairing the HR process and exacerbating DNA damage. Additionally, SJNP releases cinnamaldehyde (CA) upon CT linkage cleavage, elevating intracellular ROS levels in a self-amplifying manner and inducing ROS-mediated mitochondrial dysfunction. Our results indicate that SJNP effectively targets murine triple-negative breast cancer (TNBC) with minimal adverse toxicity, showcasing its potential as a formidable opponent in the fight against cancer.


Assuntos
Acroleína , Camptotecina , Sistemas de Liberação de Medicamentos , Nanopartículas , Neoplasias de Mama Triplo Negativas , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Nanopartículas/administração & dosagem , Nanopartículas/química , Animais , Humanos , Feminino , Linhagem Celular Tumoral , Acroleína/análogos & derivados , Acroleína/administração & dosagem , Acroleína/química , Camptotecina/análogos & derivados , Camptotecina/administração & dosagem , Camptotecina/uso terapêutico , Camptotecina/farmacologia , Pró-Fármacos/administração & dosagem , Pró-Fármacos/uso terapêutico , Ácido Linoleico/química , Ácido Linoleico/administração & dosagem , Triazóis/administração & dosagem , Triazóis/farmacologia , Triazóis/química , Dano ao DNA/efeitos dos fármacos , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Camundongos Nus , Camundongos , Proteínas de Ciclo Celular/metabolismo , Fatores de Transcrição/metabolismo , Inibidores da Topoisomerase I/administração & dosagem , Proteínas que Contêm Bromodomínio , Azepinas
3.
PLoS One ; 19(6): e0304985, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38843278

RESUMO

Signal regulatory protein alpha (SIRPα) is an immune inhibitory receptor on myeloid cells including macrophages and dendritic cells, which binds to CD47, a ubiquitous self-associated molecule. SIRPα-CD47 interaction is exploited by cancer cells to suppress anti-tumor activity of myeloid cells, therefore emerging as a novel immune checkpoint for cancer immunotherapy. In blood cancer, several SIRPα-CD47 blockers have shown encouraging monotherapy activity. However, the anti-tumor activity of SIRPα-CD47 blockers in solid tumors seems limited, suggesting the need for combination therapies to fully exploit the myeloid immune checkpoint in solid tumors. Here we tested whether combination of SIRPα-CD47 blocker with antibody-drug conjugate bearing a topoisomerase I inhibitor DXd (DXd-ADC) would enhance anti-tumor activity in solid tumors. To this end, DS-1103a, a newly developed anti-human SIRPα antibody (Ab), was assessed for the potential combination benefit with datopotamab deruxtecan (Dato-DXd) and trastuzumab deruxtecan (T-DXd), DXd-ADCs targeting human trophoblast cell-surface antigen 2 and human epidermal growth factor receptor 2, respectively. DS-1103a inhibited SIRPα-CD47 interaction and enhanced antibody-dependent cellular phagocytosis of Dato-DXd and T-DXd against human cancer cells. In a whole cancer cell vaccination model, vaccination with DXd-treated cancer cells led to activation of tumor-specific T cells when combined with an anti-mouse SIRPα (anti-mSIRPα) Ab, implying the benefit of combining DXd-ADCs with anti-SIRPα Ab on anti-tumor immunity. Furthermore, in syngeneic mouse models, both Dato-DXd and T-DXd combination with anti-mSIRPα Ab showed stronger anti-tumor activity over the monotherapies. Taken together, this study provides a preclinical rationale of novel therapies for solid tumors combining SIRPα-CD47 blockers with DXd-ADCs.


Assuntos
Antígenos de Diferenciação , Antígeno CD47 , Imunoconjugados , Receptores Imunológicos , Antígeno CD47/antagonistas & inibidores , Antígeno CD47/imunologia , Animais , Receptores Imunológicos/antagonistas & inibidores , Receptores Imunológicos/metabolismo , Receptores Imunológicos/imunologia , Humanos , Camundongos , Imunoconjugados/farmacologia , Antígenos de Diferenciação/imunologia , Linhagem Celular Tumoral , Feminino , Trastuzumab/farmacologia , Inibidores da Topoisomerase I/farmacologia , Imunoterapia/métodos , Camundongos Endogâmicos BALB C
4.
Sci Rep ; 14(1): 14000, 2024 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-38890412

RESUMO

Intratumoral (IT) therapy is a powerful method of controlling tumor growth, but a major unsolved problem is the rapidity that injected drugs exit tumors, limiting on-target exposure and efficacy. We have developed a generic long acting IT delivery system in which a drug is covalently tethered to hydrogel microspheres (MS) by a cleavable linker; upon injection the conjugate forms a depot that slowly releases the drug and "bathes" the tumor for long periods. We established technology to measure tissue pharmacokinetics and studied MSs attached to SN-38, a topoisomerase 1 inhibitor. When MS ~ SN-38 was injected locally, tissues showed high levels of SN-38 with a long half-life of ~ 1 week. IT MS ~ SN-38 was ~ tenfold more efficacious as an anti-tumor agent than systemic SN-38. We also propose and provide an example that long-acting IT therapy might enable safe use of two drugs with overlapping toxicities. Here, long-acting IT MS ~ SN-38 is delivered with concurrent systemic PARP inhibitor. The tumor is exposed to both drugs whereas other tissues are exposed only to the systemic drug; synergistic anti-tumor activity supported the validity of this approach. We propose use of this approach to increase efficacy and reduce toxicities of combinations of immune checkpoint inhibitors such as αCTLA-4 and αPD-1.


Assuntos
Irinotecano , Animais , Camundongos , Humanos , Irinotecano/administração & dosagem , Irinotecano/farmacocinética , Microesferas , Hidrogéis/química , Linhagem Celular Tumoral , Inibidores da Topoisomerase I/administração & dosagem , Inibidores da Topoisomerase I/farmacocinética , Inibidores da Topoisomerase I/uso terapêutico , Sistemas de Liberação de Medicamentos , Feminino , Neoplasias/tratamento farmacológico , Ensaios Antitumorais Modelo de Xenoenxerto , Injeções Intralesionais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia
5.
Bioorg Chem ; 147: 107412, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38696845

RESUMO

The development of novel topoisomerase I (TOP1) inhibitors is crucial for overcoming the drawbacks and limitations of current TOP1 poisons. Here, we identified two potential TOP1 inhibitors, namely, FTY720 (a sphingosine 1-phosphate antagonist) and COH29 (a ribonucleotide reductase inhibitor), through experimental screening of known active compounds. Biological experiments verified that FTY720 and COH29 were nonintercalative TOP1 catalytic inhibitors that did not induce the formation of DNA-TOP1 covalent complexes. Molecular docking revealed that FTY720 and COH29 interacted favorably with TOP1. Molecular dynamics simulations revealed that FTY720 and COH29 could affect the catalytic domain of TOP1, thus resulting in altered DNA-binding cavity size. The alanine scanning and interaction entropy identified Arg536 as a hotspot residue. In addition, the bioinformatics analysis predicted that FTY720 and COH29 could be effective in treating malignant breast tumors. Biological experiments verified their antitumor activities using MCF-7 breast cancer cells. Their combinatory effects with TOP1 poisons were also investigated. Further, FTY720 and COH29 were found to cause less DNA damage compared with TOP1 poisons. The findings provide reliable lead compounds for the development of novel TOP1 catalytic inhibitors and offer new insights into the potential clinical applications of FTY720 and COH29 in targeting TOP1.


Assuntos
Antineoplásicos , DNA Topoisomerases Tipo I , Cloridrato de Fingolimode , Simulação de Acoplamento Molecular , Inibidores da Topoisomerase I , Humanos , Cloridrato de Fingolimode/farmacologia , Cloridrato de Fingolimode/química , Cloridrato de Fingolimode/síntese química , DNA Topoisomerases Tipo I/metabolismo , DNA Topoisomerases Tipo I/química , Inibidores da Topoisomerase I/farmacologia , Inibidores da Topoisomerase I/química , Inibidores da Topoisomerase I/síntese química , Estrutura Molecular , Relação Estrutura-Atividade , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Proliferação de Células/efeitos dos fármacos , Simulação de Dinâmica Molecular , Células MCF-7
6.
Mol Pharm ; 21(7): 3240-3255, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38785196

RESUMO

Inhibitors of a DNA repair enzyme known as polynucleotide kinase 3'-phosphatase (PNKP) are expected to show synergistic cytotoxicity in combination with topoisomerase I (TOP1) inhibitors in cancer. In this study, the synergistic cytotoxicity of a novel inhibitor of PNKP, i.e., A83B4C63, with a potent TOP1 inhibitor, i.e., SN-38, against colorectal cancer cells was investigated. Polymeric micelles (PMs) for preferred tumor delivery of A83B4C63, developed through physical encapsulation of this compound in methoxy poly(ethylene oxide)-poly(α-benzyl carboxylate-ε-caprolactone) (mPEO-b-PBCL) micelles, were combined with SN-38 in free or PM form. The PM form of SN-38 was prepared through chemical conjugation of SN-38 to the functional end group of mPEO-b-PBCL and further assembly of mPEO-b-PBCL-SN-38 in water. Moreover, mixed micelles composed of mPEO-b-PBCL and mPEO-b-PBCL-SN-38 were used to co-load A83B4C63 and SN-38 in the same nanoformulation. The loading content (% w/w) of the SN-38 and A83B4C63 to mPEO-b-PBCL in the co-loaded formulation was 7.91 ± 0.66 and 16.13 ± 0.11% (w/w), respectively, compared to 15.67 ± 0.34 (% w/w) and 23.06 ± 0.63 (% w/w) for mPEO-b-PBCL micelles loading individual drugs. Notably, the average diameter of PMs co-encapsulating both SN-38 and A83B4C63 was larger than that of PMs encapsulating either of these compounds alone but still lower than 60 nm. The release of A83B4C63 from PMs co-encapsulating both drugs was 76.36 ± 1.41% within 24 h, which was significantly higher than that of A83B4C63-encapsulated micelles (42.70 ± 0.72%). In contrast, the release of SN-38 from PMs co-encapsulating both drugs was 44.15 ± 2.61% at 24 h, which was significantly lower than that of SN-38-conjugated PMs (74.16 ± 3.65%). Cytotoxicity evaluations by the MTS assay as analyzed by the Combenefit software suggested a clear synergy between PM/A83B4C63 (at a concentration range of 10-40 µM) and free SN-38 (at a concentration range of 0.001-1 µM). The synergistic cytotoxic concentration range for SN-38 was narrowed down to 0.1-1 or 0.01-1 µM when combined with PM/A83B4C63 at 10 or 20-40 µM, respectively. In general, PMs co-encapsulating A83B4C63 and SN-38 at drug concentrations within the synergistic range (10 µM for A83B4C63 and 0.05-1 µM for SN-38) showed slightly less enhancement of SN-38 anticancer activity than a combination of individual micelles, i.e., A83B4C63 PMs + SN-38 PMs at the same molar concentrations. This was attributed to the slower release of SN-38 from the SN-38 and A83B4C63 co-encapsulated PMs compared to PMs only encapsulating SN-38. Cotreatment of cells with TOP1 inhibitors and A83B4C63 formulation enhanced the expression level of γ-HA2X, cleaved PARP, caspase-3, and caspase-7 in most cases. This trend was more consistent and notable for PMs co-encapsulating both A83B4C63 and SN-38. The overall result from the study shows a synergy between PMs of SN-38 and A83B4C63 as a mixture of two PMs for individual drugs or PMs co-encapsulating both drugs.


Assuntos
Neoplasias Colorretais , Irinotecano , Micelas , Inibidores da Topoisomerase I , Humanos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Irinotecano/farmacologia , Irinotecano/administração & dosagem , Inibidores da Topoisomerase I/farmacologia , Inibidores da Topoisomerase I/administração & dosagem , Inibidores da Topoisomerase I/química , Linhagem Celular Tumoral , Animais , Camundongos , Nanomedicina/métodos , Sinergismo Farmacológico , DNA Topoisomerases Tipo I/metabolismo , Nanopartículas/química , Ensaios Antitumorais Modelo de Xenoenxerto , Poliésteres/química , Fosfotransferases (Aceptor do Grupo Álcool) , Enzimas Reparadoras do DNA
7.
Chemistry ; 30(39): e202401400, 2024 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-38736421

RESUMO

Coumestan represents a biologically relevant structural motif distributed in a number of natural products, and the rapid construction of related derivatives as well as the characterization of targets would accelerate lead compound discovery in medicinal chemistry. In this work, a general and scalable approach to 8,9-dihydroxycoumestans via two-electrode constant current electrolysis was developed. The application of a two-phase (aqueous/organic) system plays a crucial role for success, protecting the sensitive o-benzoquinone intermediates from over-oxidation. Based on the structurally diverse products, a primary SAR study on coumestan scaffold was completed, and compound 3 r exhibited potent antiproliferative activities and a robust topoisomerase I (Top1) inhibitory activity. Further mechanism studies demonstrates that compound 3 r was a novel Top1 poison, which might open an avenue for the development of Top1-targeted antitumor agent.


Assuntos
Antineoplásicos , Cumarínicos , DNA Topoisomerases Tipo I , Inibidores da Topoisomerase I , Inibidores da Topoisomerase I/química , Inibidores da Topoisomerase I/farmacologia , Inibidores da Topoisomerase I/síntese química , DNA Topoisomerases Tipo I/metabolismo , DNA Topoisomerases Tipo I/química , Humanos , Relação Estrutura-Atividade , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Cumarínicos/química , Cumarínicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Oxirredução , Umbeliferonas/química , Umbeliferonas/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais
8.
Clin Cancer Res ; 30(14): 2917-2924, 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-38709212

RESUMO

PURPOSE: The antibody-drug conjugate (ADC) sacituzumab govitecan (SG) comprises the topoisomerase 1 (TOP1) inhibitor (TOP1i) SN-38, coupled to a monoclonal antibody targeting trophoblast cell surface antigen 2 (TROP-2). Poly(ADP-ribose) polymerase (PARP) inhibition may synergize with TOP1i and SG, but previous studies combining systemic PARP and TOP1 inhibitors failed due to dose-limiting myelosuppression. Here, we assess the proof-of-mechanism and clinical feasibility for SG and talazoparib (TZP) employing an innovative sequential dosing schedule. PATIENTS AND METHODS: In vitro models tested pharmacodynamic endpoints, and in a phase 1b clinical trial (NCT04039230), 30 patients with metastatic triple-negative breast cancer (mTNBC) received SG and TZP in a concurrent (N = 7) or sequential (N = 23) schedule. Outcome measures included safety, tolerability, preliminary efficacy, and establishment of a recommended phase 2 dose. RESULTS: We hypothesized that tumor-selective delivery of TOP1i via SG would reduce nontumor toxicity and create a temporal window, enabling sequential dosing of SG and PARP inhibition. In vitro, sequential SG followed by TZP delayed TOP1 cleavage complex clearance, increased DNA damage, and promoted apoptosis. In the clinical trial, sequential SG/TZP successfully met primary objectives and demonstrated median progression-free survival (PFS) of 7.6 months without dose-limiting toxicities (DLT), while concurrent dosing yielded 2.3 months PFS and multiple DLTs including severe myelosuppression. CONCLUSIONS: While SG dosed concurrently with TZP is not tolerated clinically due to an insufficient therapeutic window, sequential dosing of SG followed by TZP proved a viable strategy. These findings support further clinical development of the combination and suggest that ADC-based therapy may facilitate novel, mechanism-based dosing strategies.


Assuntos
Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Camptotecina , Imunoconjugados , Inibidores de Poli(ADP-Ribose) Polimerases , Inibidores da Topoisomerase I , Humanos , Feminino , Imunoconjugados/administração & dosagem , Imunoconjugados/uso terapêutico , Imunoconjugados/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Pessoa de Meia-Idade , Anticorpos Monoclonais Humanizados/administração & dosagem , Camptotecina/análogos & derivados , Camptotecina/administração & dosagem , Camptotecina/uso terapêutico , Idoso , Inibidores da Topoisomerase I/administração & dosagem , Inibidores da Topoisomerase I/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Adulto , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Ftalazinas/administração & dosagem , Linhagem Celular Tumoral , DNA Topoisomerases Tipo I/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Antígenos de Neoplasias/imunologia , Moléculas de Adesão Celular
9.
Cancer Immunol Immunother ; 73(5): 92, 2024 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-38564022

RESUMO

Current immune checkpoint inhibiters (ICIs) have contrasting clinical results in poorly immunogenic cancers such as microsatellite-stable colorectal cancer (MSS-CRC). Therefore, understanding and developing the combinational therapeutics for ICI-unresponsive cancers is critical. Here, we demonstrated that the novel topoisomerase I inhibitor TLC388 can reshape the tumor immune landscape, corroborating their antitumor effects combined with radiotherapy as well as immunotherapy. We found that TLC388 significantly triggered cytosolic single-stranded DNA (ssDNA) accumulation for STING activation, leading to type I interferons (IFN-Is) production for increased cancer immunogenicity to enhance antitumor immunity. TLC388-treated tumors were infiltrated by a vast number of dendritic cells, immune cells, and costimulatory molecules, contributing to the favorable antitumor immune response within the tumor microenvironment. The infiltration of cytotoxic T and NK cells were more profoundly existed within tumors in combination with radiotherapy and ICIs, leading to superior therapeutic efficacy in poorly immunogenic MSS-CRC. Taken together, these results showed that the novel topoisomerase I inhibitor TLC388 increased cancer immunogenicity by ssDNA/STING-mediated IFN-I production, enhancing antitumor immunity for better therapeutic efficacy in combination with radiotherapy and ICIs for poorly immunogenic cancer.


Assuntos
Camptotecina/análogos & derivados , Neoplasias Colorretais , Inibidores da Topoisomerase I , Humanos , Inibidores da Topoisomerase I/farmacologia , Inibidores da Topoisomerase I/uso terapêutico , Neoplasias Colorretais/terapia , Citosol , Microambiente Tumoral
10.
J Transl Med ; 22(1): 362, 2024 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-38632563

RESUMO

BACKGROUND: HER3 (ErbB3), a member of the human epidermal growth factor receptor family, is frequently overexpressed in various cancers. Multiple HER3-targeting antibodies and antibody-drug conjugates (ADCs) were developed for the solid tumor treatment, however none of HER3-targeting agent has been approved for tumor therapy yet. We developed DB-1310, a HER3 ADC composed of a novel humanized anti-HER3 monoclonal antibody covalently linked to a proprietary DNA topoisomerase I inhibitor payload (P1021), and evaluate the efficacy and safety of DB-1310 in preclinical models. METHODS: The binding of DB-1310 to Her3 and other HER families were measured by ELISA and SPR. The competition of binding epitope for DB-1310 and patritumab was tested by FACS. The sensitivity of breast, lung, prostate and colon cancer cell lines to DB-1310 was evaluated by in vitro cell killing assay. In vivo growth inhibition study evaluated the sensitivity of DB-1310 to Her3 + breast, lung, colon and prostate cancer xenograft models. The safety profile was also measured in cynomolgus monkey. RESULTS: DB-1310 binds HER3 via a novel epitope with high affinity and internalization capacity. In vitro, DB-1310 exhibited cytotoxicity in numerous HER3 + breast, lung, prostate and colon cancer cell lines. In vivo studies in HER3 + HCC1569 breast cancer, NCI-H441 lung cancer and Colo205 colon cancer xenograft models showed DB-1310 to have dose-dependent tumoricidal activity. Tumor suppression was also observed in HER3 + non-small cell lung cancer (NSCLC) and prostate cancer patient-derived xenograft (PDX) models. Moreover, DB-1310 showed stronger tumor growth-inhibitory activity than patritumab deruxtecan (HER3-DXd), which is another HER3 ADC in clinical development at the same dose. The tumor-suppressive activity of DB-1310 synergized with that of EGFR tyrosine kinase inhibitor, osimertinib, and exerted efficacy also in osimertinib-resistant PDX model. The preclinical assessment of safety in cynomolgus monkeys further revealed DB-1310 to have a good safety profile with a highest non severely toxic dose (HNSTD) of 45 mg/kg. CONCLUSIONS: These finding demonstrated that DB-1310 exerted potent antitumor activities against HER3 + tumors in in vitro and in vivo models, and showed acceptable safety profiles in nonclinical species. Therefore, DB-1310 may be effective for the clinical treatment of HER3 + solid tumors.


Assuntos
Acrilamidas , Compostos de Anilina , Carcinoma Pulmonar de Células não Pequenas , Neoplasias do Colo , Imunoconjugados , Indóis , Neoplasias Pulmonares , Neoplasias da Próstata , Pirimidinas , Inibidores da Topoisomerase I , Animais , Humanos , Masculino , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células , Epitopos , Imunoconjugados/farmacologia , Imunoconjugados/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Macaca fascicularis/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Receptor ErbB-3 , Inibidores da Topoisomerase I/farmacologia , Inibidores da Topoisomerase I/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
11.
J Photochem Photobiol B ; 255: 112910, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38663337

RESUMO

The prognosis for patients with advanced-stage pancreatic ductal adenocarcinoma (PDAC) remains dismal. It is generally accepted that combination cancer therapies offer the most promise, such as Folforinox, despite their associated high toxicity. This study addresses the issue of chemoresistance by introducing a complementary dual priming approach to attenuate the DNA repair mechanism and to improve the efficacy of a type 1 topoisomerase (Top1) inhibitor. The result is a regimen that integrates drug-repurposing and nanotechnology using 3 clinically relevant FDA-approved agents (1) Top1 inhibitor (irinotecan) at subcytotoxic doses (2) benzoporphyrin derivative (BPD) as a photoactive molecule for photodynamic priming (PDP) to improve the delivery of irinotecan within the cancer cell and (3) minocycline priming (MNP) to modulate DNA repair enzyme Tdp1 (tyrosyl-DNA phosphodiesterase) activity. We demonstrate in heterotypic 3D cancer models that incorporate cancer cells and pancreatic cancer-associated fibroblasts that simultaneous targeting of Tdp1 and Top1 were significantly more effective by employing MNP and photoactivatable multi-inhibitor liposomes encapsulating BPD and irinotecan compared to monotherapies or a cocktail of dual or triple-agents. These data are encouraging and warrant further work in appropriate animal models to evolve improved therapeutic regimens.


Assuntos
Carcinoma Ductal Pancreático , Irinotecano , Minociclina , Neoplasias Pancreáticas , Fotoquimioterapia , Humanos , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/metabolismo , Linhagem Celular Tumoral , Minociclina/farmacologia , Minociclina/uso terapêutico , Irinotecano/farmacologia , Irinotecano/uso terapêutico , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/patologia , Diester Fosfórico Hidrolases/metabolismo , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/uso terapêutico , Inibidores da Topoisomerase I/farmacologia , Inibidores da Topoisomerase I/uso terapêutico , Inibidores da Topoisomerase I/química , Lipossomos/química
12.
Eur J Pharmacol ; 974: 176614, 2024 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-38677535

RESUMO

Irinotecan (also known as CPT-11) is a topoisomerase I inhibitor first approved for clinical use as an anticancer agent in 1996. Over the past more than two decades, it has been widely used for combination regimens to treat various malignancies, especially in gastrointestinal and lung cancers. However, severe dose-limiting toxicities, especially gastrointestinal toxicity such as late-onset diarrhea, were frequently observed in irinotecan-based therapy, thus largely limiting the clinical application of this agent. Current knowledge regarding the pathogenesis of irinotecan-induced diarrhea is characterized by the complicated metabolism of irinotecan to its active metabolite SN-38 and inactive metabolite SN-38G. A series of enzymes and transporters were involved in these metabolic processes, including UGT1A1 and CYP3A4. Genetic polymorphisms of these metabolizing enzymes were significantly associated with the occurrence of irinotecan-induced diarrhea. Recent discoveries and progress made on the detailed mechanisms enable the identification of potential biomarkers for predicting diarrhea and as such guiding the proper patient selection with a better range of tolerant dosages. In this review, we introduce the metabolic process of irinotecan and describe the pathogenic mechanisms underlying irinotecan-induced diarrhea. Based on the mechanisms, we further outline the potential biomarkers for predicting the severity of diarrhea. Finally, based on the current experimental evidence in preclinical and clinical studies, we discuss and prospect the current and emerging strategies for the prevention of irinotecan-induced diarrhea.


Assuntos
Diarreia , Glucuronosiltransferase , Irinotecano , Irinotecano/efeitos adversos , Diarreia/induzido quimicamente , Diarreia/tratamento farmacológico , Humanos , Animais , Glucuronosiltransferase/genética , Glucuronosiltransferase/metabolismo , Inibidores da Topoisomerase I/efeitos adversos , Inibidores da Topoisomerase I/uso terapêutico , Citocromo P-450 CYP3A/metabolismo , Citocromo P-450 CYP3A/genética
13.
J Clin Oncol ; 42(19): 2317-2326, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38648575

RESUMO

PURPOSE: The phase III RESILIENT trial compared second-line liposomal irinotecan with topotecan in patients with small cell lung cancer (SCLC). PATIENTS AND METHODS: Patients with SCLC and progression on or after first-line platinum-based chemotherapy were randomly assigned (1:1) to intravenous (IV) liposomal irinotecan (70 mg/m2 every 2 weeks in a 6-week cycle) or IV topotecan (1.5 mg/m2 daily for 5 consecutive days, every 3 weeks in a 6-week cycle). The primary end point was overall survival (OS). Key secondary end points included progression-free survival (PFS) and objective response rate (ORR). RESULTS: Among 461 randomly assigned patients, 229 received liposomal irinotecan and 232 received topotecan. The median follow-up was 18.4 months. The median OS was 7.9 months with liposomal irinotecan versus 8.3 months with topotecan (hazard ratio [HR], 1.11 [95% CI, 0.90 to 1.37]; P = .31). The median PFS per blinded independent central review (BICR) was 4.0 months with liposomal irinotecan and 3.3 months with topotecan (HR, 0.96 [95% CI, 0.77 to 1.20]; nominal P = .71); ORR per BICR was 44.1% (95% CI, 37.6 to 50.8) and 21.6% (16.4 to 27.4), respectively. Overall, 42.0% and 83.4% of patients receiving liposomal irinotecan and topotecan, respectively, experienced grade ≥3 related treatment-emergent adverse events (TEAEs). The most common grade ≥3 related TEAEs were diarrhea (13.7%), neutropenia (8.0%), and decreased neutrophil count (4.4%) with liposomal irinotecan and neutropenia (51.6%), anemia (30.9%), and leukopenia (29.1%) with topotecan. CONCLUSION: Liposomal irinotecan and topotecan demonstrated similar median OS and PFS in patients with relapsed SCLC. Although the primary end point of OS was not met, liposomal irinotecan demonstrated a higher ORR than topotecan. The safety profile of liposomal irinotecan was consistent with its known safety profile; no new safety concerns emerged.


Assuntos
Irinotecano , Lipossomos , Neoplasias Pulmonares , Recidiva Local de Neoplasia , Carcinoma de Pequenas Células do Pulmão , Topotecan , Humanos , Topotecan/administração & dosagem , Topotecan/efeitos adversos , Irinotecano/administração & dosagem , Irinotecano/efeitos adversos , Irinotecano/uso terapêutico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/mortalidade , Carcinoma de Pequenas Células do Pulmão/patologia , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/mortalidade , Adulto , Recidiva Local de Neoplasia/tratamento farmacológico , Idoso de 80 Anos ou mais , Intervalo Livre de Progressão , Inibidores da Topoisomerase I/administração & dosagem , Inibidores da Topoisomerase I/efeitos adversos , Inibidores da Topoisomerase I/uso terapêutico
14.
Fitoterapia ; 175: 105921, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38561052

RESUMO

Sophoridine, which is derived from the Leguminous plant Sophora alopecuroides L., has certain pharmacological activity as a new anticancer drug. Herein, a series of novel N-substituted sophoridine derivatives was designed, synthesized and evaluated with anticancer activity. Through QSAR prediction models, it was discovered that the introduction of a benzene ring as a main pharmacophore and reintroduced into a benzene in para position on the phenyl ring in the novel sophoridine derivatives improved the anticancer activity effectively. In vitro, 28 novel compounds were evaluated for anticancer activity against four human tumor cell lines (A549, CNE-2, HepG-2, and HEC-1-B). In particular, Compound 26 exhibited remarkable inhibitory effects, with an IC50 value of 15.6 µM against HepG-2 cells, surpassing cis-Dichlorodiamineplatinum (II). Molecular docking studies verified that the derivatives exhibit stronger binding affinity with DNA topoisomerase I compared to sophoridine. In addition, 26 demonstrated significant inhibition of DNA Topoisomerase I and could arrest cells in G0/G1 phase. This study provides valuable insights into the design and synthesis of N-substituted sophoridine derivatives with anticancer activity.


Assuntos
Alcaloides , Matrinas , Simulação de Acoplamento Molecular , Relação Quantitativa Estrutura-Atividade , Quinolizinas , Sophora , Inibidores da Topoisomerase I , Humanos , Inibidores da Topoisomerase I/farmacologia , Inibidores da Topoisomerase I/síntese química , Quinolizinas/farmacologia , Quinolizinas/síntese química , Quinolizinas/química , Estrutura Molecular , Sophora/química , Alcaloides/farmacologia , Alcaloides/síntese química , Alcaloides/química , Linhagem Celular Tumoral , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/síntese química , Indolizinas/farmacologia , Indolizinas/química , Indolizinas/síntese química , DNA Topoisomerases Tipo I/metabolismo , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/síntese química
15.
J Med Chem ; 67(9): 7006-7032, 2024 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-38668707

RESUMO

G-quadruplexes are noncanonical four-stranded DNA secondary structures. MYC is a master oncogene and the G-quadruplex formed in the MYC promoter functions as a transcriptional silencer and can be stabilized by small molecules. We have previously revealed a novel mechanism of action for indenoisoquinoline anticancer drugs, dual-downregulation of MYC and inhibition of topoisomerase I. Herein, we report the design and synthesis of novel 7-aza-8,9-methylenedioxyindenoisoquinolines based on desirable substituents and π-π stacking interactions. These compounds stabilize the MYC promoter G-quadruplex, significantly lower MYC levels in cancer cells, and inhibit topoisomerase I. MYC targeting was demonstrated by differential activities in Raji vs CA-46 cells and cytotoxicity in MYC-dependent cell lines. Cytotoxicities in the NCI-60 panel of human cancer cell lines were investigated. Favorable pharmacokinetics were established, and in vivo anticancer activities were demonstrated in xenograft mouse models. Furthermore, favorable brain penetration, brain pharmacokinetics, and anticancer activity in an orthotopic glioblastoma mouse model were demonstrated.


Assuntos
Antineoplásicos , Desenho de Fármacos , Quadruplex G , Isoquinolinas , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-myc , Inibidores da Topoisomerase I , Quadruplex G/efeitos dos fármacos , Humanos , Animais , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Isoquinolinas/farmacologia , Isoquinolinas/química , Isoquinolinas/farmacocinética , Isoquinolinas/síntese química , Camundongos , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Inibidores da Topoisomerase I/farmacologia , Inibidores da Topoisomerase I/síntese química , Inibidores da Topoisomerase I/farmacocinética , Inibidores da Topoisomerase I/química , Inibidores da Topoisomerase I/uso terapêutico , Relação Estrutura-Atividade , DNA Topoisomerases Tipo I/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Mol Cancer Ther ; 23(6): 751-765, 2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38588408

RESUMO

A majority of patients with cancer receive radiotherapy as part of their treatment regimens whether using external beam therapy or locally-delivered radioisotopes. While often effective, some tumors are inadequately controlled with radiation and radiotherapy has significant short-term and long-term toxicities for cancer survivors. Insights into molecular mechanisms involved in cellular responses to DNA breaks introduced by radiation or other cancer therapies have been gained in recent years and approaches to manipulate these responses to enhance tumor cell killing or reduce normal tissue toxicity are of great interest. Here, we report the identification and initial characterization of XRD-0394, a potent and specific dual inhibitor of two DNA damage response kinases, ATM and DNA-PKcs. This orally bioavailable molecule demonstrates significantly enhanced tumor cell kill in the setting of therapeutic ionizing irradiation in vitro and in vivo. XRD-0394 also potentiates the effectiveness of topoisomerase I inhibitors in vitro. In addition, in cells lacking BRCA1/2 XRD-0394 shows single-agent activity and synergy in combination with PARP inhibitors. A phase Ia clinical trial (NCT05002140) with XRD-0394 in combination with radiotherapy has completed. These results provide a rationale for future clinical trials with XRD-0394 in combination with radiotherapy, PARP inhibitors, and targeted delivery of topoisomerase I inhibitors.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia , Proteína Quinase Ativada por DNA , Inibidores de Poli(ADP-Ribose) Polimerases , Radiossensibilizantes , Inibidores da Topoisomerase I , Humanos , Animais , Inibidores da Topoisomerase I/farmacologia , Camundongos , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Radiossensibilizantes/farmacologia , Proteína Quinase Ativada por DNA/antagonistas & inibidores , Proteína Quinase Ativada por DNA/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Linhagem Celular Tumoral , Feminino , Sinergismo Farmacológico
17.
Drug Metab Pharmacokinet ; 56: 101001, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38643548

RESUMO

Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate used for cancer treatment comprising an anti-human epidermal growth factor receptor type 2 (HER2) antibody and the topoisomerase I inhibitor DXd. The present study investigated the intratumor fate of T-DXd. Fluorescence-labeled T-DXd was found to accumulate in tumors of HER2-positive tumor xenograft mice and was observed to be distributed within lysosomes of in vitro tumor cells in accordance with their HER2 expression. DXd was released by cysteine proteases, including cathepsins, in lysosomal fractions in vitro in response to the pH. Tumor slices obtained from HER2-positive tumor xenograft mice treated with T-DXd were examined by semi-quantitative and three-dimensional immunohistochemical assays using phosphor-integrated dots, which visualized DXd-related signals in the nucleus, the site of topoisomerase I inhibition. In addition, based on the data showing the antibody component of T-DXd barely distributed in the nucleus, it was suggested that the DXd-related signals detected in the nucleus were predominantly derived from free DXd. These observations help support the mode of action of T-DXd from the perspective of drug disposition.


Assuntos
Camptotecina , Imunoconjugados , Trastuzumab , Ensaios Antitumorais Modelo de Xenoenxerto , Trastuzumab/farmacologia , Animais , Humanos , Camundongos , Camptotecina/análogos & derivados , Camptotecina/farmacologia , Camptotecina/metabolismo , Imunoconjugados/farmacologia , Feminino , Camundongos Nus , Inibidores da Topoisomerase I/farmacologia , Inibidores da Topoisomerase I/metabolismo , Receptor ErbB-2/metabolismo , Receptor ErbB-2/antagonistas & inibidores , Linhagem Celular Tumoral , Camundongos Endogâmicos BALB C , Antineoplásicos Imunológicos/farmacologia
18.
Bioorg Med Chem Lett ; 104: 129710, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38518997

RESUMO

A novel series of benzo[6,7]indolo[3,4-c]isoquinolines 3a-3f was designed by scaffold hopping of topoisomerase I inhibitor benzo[g][1]benzopyrano[4,3-b]indol-6(13H)-ones (BBPIs), which were developed by structural modification of the natural marine product lamellarin. The unconventional pentacycle was constructed by Bischler-Napieralski-type condensation of amide 11 and subsequent intramolecular Heck reaction. In vitro anticancer activity of the synthesized benzo[6,7]indolo[3,4-c]isoquinolines was evaluated on a panel of 39 human cancer cell lines (JFCR39). Among the compounds tested, N-(3-morpholinopropyl) derivative 3e showed the most potent antiproliferative activity, with a mean GI50 value of 39 nM. This compound inhibited topoisomerase I activity by stabilizing the enzyme-DNA complex.


Assuntos
Antineoplásicos , Cumarínicos , Compostos Heterocíclicos de 4 ou mais Anéis , Isoquinolinas , Inibidores da Topoisomerase I , Humanos , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , DNA Topoisomerases Tipo I/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Isoquinolinas/síntese química , Isoquinolinas/química , Isoquinolinas/farmacologia , Relação Estrutura-Atividade , Inibidores da Topoisomerase I/síntese química , Inibidores da Topoisomerase I/química , Inibidores da Topoisomerase I/farmacologia , Desenho de Fármacos , Cumarínicos/síntese química , Cumarínicos/química , Cumarínicos/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Compostos Heterocíclicos de 4 ou mais Anéis/química , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia
19.
Pharm Res ; 41(4): 795-806, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38536615

RESUMO

PURPOSE: Quantifying unencapsulated drug concentrations in tissues is crucial for understanding the mechanisms underlying the efficacy and safety of liposomal drugs; however, the methodology for this has not been fully established. Herein, we aimed to investigate the enhanced therapeutic potential of a pegylated liposomal formulation of topotecan (FF-10850) by analyzing the concentrations of the unencapsulated drug in target tissues, to guide the improvement of its dosing regimen. METHODS: We developed a method for measuring unencapsulated topotecan concentrations in tumor and bone marrow interstitial fluid (BM-ISF) and applied this method to pharmacokinetic assessments. The ratios of the area under the concentration-time curves (AUCs) between tumor and BM-ISF were calculated for total and unencapsulated topotecan. DNA damage and antitumor effects of FF-10850 or non-liposomal topotecan (TPT) were evaluated in an ES-2 mice xenograft model. RESULTS: FF-10850 exhibited a much larger AUC ratio between tumor and BM-ISF for unencapsulated topotecan (2.96), but not for total topotecan (0.752), than TPT (0.833). FF-10850 promoted milder DNA damage in the bone marrow than TPT; however, FF-10850 and TPT elicited comparable DNA damage in the tumor. These findings highlight the greater tumor exposure to unencapsulated topotecan and lower bone marrow exposure to FF-10850 than TPT. The dosing regimen was successfully improved based on the kinetics of unencapsulated topotecan and DNA damage. CONCLUSIONS: Tissue pharmacokinetics of unencapsulated topotecan elucidated the favorable pharmacological properties of FF-10850. Evaluation of tissue exposure to an unencapsulated drug with appropriate pharmacodynamic markers can be valuable in optimizing liposomal drugs and dosing regimens.


Assuntos
Antineoplásicos , Neoplasias , Humanos , Camundongos , Animais , Topotecan/farmacocinética , Inibidores da Topoisomerase I/farmacocinética , Lipossomos , Neoplasias/tratamento farmacológico , Modelos Animais de Doenças , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico
20.
Nucleic Acids Res ; 52(5): 2142-2156, 2024 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-38340342

RESUMO

Human DNA topoisomerase 1 (Top1) is a crucial enzyme responsible for alleviating torsional stress on DNA during transcription and replication, thereby maintaining genome stability. Previous researches had found that non-working Top1 interacted extensively with chromosomal DNA in human cells. However, the reason for its retention on chromosomal DNA remained unclear. In this study, we discovered a close association between Top1 and chromosomal DNA, specifically linked to the presence of G-quadruplex (G4) structures. G4 structures, formed during transcription, trap Top1 and hinder its ability to relax neighboring DNAs. Disruption of the Top1-G4 interaction using G4 ligand relieved the inhibitory effect of G4 on Top1 activity, resulting in a further reduction of R-loop levels in cells. Additionally, the activation of Top1 through the use of a G4 ligand enhanced the toxicity of Top1 inhibitors towards cancer cells. Our study uncovers a negative regulation mechanism of human Top1 and highlights a novel pathway for activating Top1.


Assuntos
DNA Topoisomerases Tipo I , Quadruplex G , Transcrição Gênica , Humanos , DNA/química , Replicação do DNA , DNA Topoisomerases Tipo I/metabolismo , Ligantes , Inibidores da Topoisomerase I/farmacologia
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