The past, present, and future of chemotherapy with a focus on individualization of drug dosing

DeRidder, Louis; Rubinson, Douglas A.; Langer, Róbert; Traverso, Giovanni

doi:10.1016/j.jconrel.2022.10.043

Cited by 12 publications

(6 citation statements)

References 226 publications

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“…Furthermore, we demonstrated that the combination of pAXL×CD3ε with trabectedin, a conventional active chemotherapeutic drug, improved the cytotoxicity of sarcoma cells. Even if the use of conventional chemotherapeutics is under interindividual variability term of efficacy and toxicity [ 65 , 66 , 67 ], our data suggest the feasibility of combinatorial treatments and are consistent with preliminary reports, which showed anti-sarcoma activity of immunotherapy/chemotherapy combination [ 68 ]. Importantly, in our in vivo model, pAXL×CD3ε guaranteed the recruitment of T lymphocytes in the tumor site and significantly inhibited the growth of sarcoma xenografts, suggesting that this strategy has the potential to also control the fast-growing tumor cells in patients.…”

Section: Discussionsupporting

confidence: 90%

The First-In-Class Anti-AXL×CD3ε Pronectin™-Based Bispecific T-Cell Engager Is Active in Preclinical Models of Human Soft Tissue and Bone Sarcomas

Polerà

Mancuso

Riillo

et al. 2023

Cancers

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Sarcomas are heterogeneous malignancies with limited therapeutic options and a poor prognosis. We developed an innovative immunotherapeutic agent, a first-in-class Pronectin™-based Bispecific T-Cell Engager (pAXL×CD3ε), for the targeting of AXL, a TAM family tyrosine kinase receptor highly expressed in sarcomas. AXL expression was first analyzed by flow cytometry, qRT-PCR, and Western blot on a panel of sarcoma cell lines. The T-cell-mediated pAXL×CD3ε cytotoxicity against sarcoma cells was investigated by flow cytometry, luminescence assay, and fluorescent microscopy imaging. The activation and degranulation of T cells induced by pAXL×CD3ε were evaluated by flow cytometry. The antitumor activity induced by pAXL×CD3ε in combination with trabectedin was also investigated. In vivo activity studies of pAXL×CD3ε were performed in immunocompromised mice (NSG), engrafted with human sarcoma cells and reconstituted with human peripheral blood mononuclear cells from healthy donors. Most sarcoma cells showed high expression of AXL. pAXL×CD3ε triggered T-lymphocyte activation and induced dose-dependent T-cell-mediated cytotoxicity. The combination of pAXL×CD3ε with trabectedin increased cytotoxicity. pAXL×CD3ε inhibited the in vivo growth of human sarcoma xenografts, increasing the survival of treated mice. Our data demonstrate the antitumor efficacy of pAXL×CD3ε against sarcoma cells, providing a translational framework for the clinical development of pAXL×CD3ε in the treatment of human sarcomas, aggressive and still-incurable malignancies.

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Section: Discussionsupporting

confidence: 90%

The First-In-Class Anti-AXL×CD3ε Pronectin™-Based Bispecific T-Cell Engager Is Active in Preclinical Models of Human Soft Tissue and Bone Sarcomas

Polerà

Mancuso

Riillo

et al. 2023

Cancers

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“…Advanced and more potent chemotherapeutic drugs have been able to succeed the previously available anticancer drugs individually or chronologically or in combination with prevailing treatments [ 9 ]. Moreover altered chemotherapeutic dose intensity tactics like intermittent administration or higher doses along with supplements and growth factors to suppress the side effects on bone marrow have proved to be effective in preventing the regrowth of tumor [ 10 – 12 ]. Regardless of this, cancer drug resistance remains to be a major hurdle in medical oncology, therefore understanding the resistance mechanisms (innate as well as acquired) and developing next-generation targeted therapies is crucial for medical need [ 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

Unveiling the mechanisms and challenges of cancer drug resistance

Khan,

Fatima,

Aisha

et al. 2024

Cell Commun Signal

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Cancer treatment faces many hurdles and resistance is one among them. Anti-cancer treatment strategies are evolving due to innate and acquired resistance capacity, governed by genetic, epigenetic, proteomic, metabolic, or microenvironmental cues that ultimately enable selected cancer cells to survive and progress under unfavorable conditions. Although the mechanism of drug resistance is being widely studied to generate new target-based drugs with better potency than existing ones. However, due to the broader flexibility in acquired drug resistance, advanced therapeutic options with better efficacy need to be explored. Combination therapy is an alternative with a better success rate though the risk of amplified side effects is commonplace. Moreover, recent groundbreaking precision immune therapy is one of the ways to overcome drug resistance and has revolutionized anticancer therapy to a greater extent with the only limitation of being individual-specific and needs further attention. This review will focus on the challenges and strategies opted by cancer cells to withstand the current therapies at the molecular level and also highlights the emerging therapeutic options -like immunological, and stem cell-based options that may prove to have better potential to challenge the existing problem of therapy resistance.

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“…Cancer is conventionally treated by a number of approaches, including surgery, radiation and chemotherapy [ 3 , 4 ]. Intravenously injected chemotherapeutics are still the mainstay of cancer treatment [ 5 ]. However, systemic drug delivery following intravenous injection for treatment of colon cancer raises major problems of drug toxicity and side effects, including nausea and vomiting, diarrhea, decreased white blood cell count, anemia, fatigue, nerve damage, pain and skin reactions [ 6 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

Development of pH-Responsive N-benzyl-N-O-succinyl Chitosan Micelles Loaded with a Curcumin Analog (Cyqualone) for Treatment of Colon Cancer

et al. 2023

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This work aimed at preparing nanomicelles from N-benzyl-N, O-succinyl chitosan (NBSCh) loaded with a curcumin analog, 2,6-bis((3-methoxy-4-hydroxyphenyl) methylene) cyclohexanone, a.k.a. cyqualone (CL), for antineoplastic colon cancer chemotherapy. The CL-loaded NBSCh micelles were spherical and less than 100 nm in size. The entrapment efficiency of CL in the micelles ranged from 13 to 39%. Drug release from pristine CL was less than 20% in PBS at pH 7.4, whereas the release from CL-NBSCh micelles was significantly higher. The release study of CL-NBSCh revealed that around 40% of CL content was released in simulated gastric fluid at pH 1.2; 79 and 85% in simulated intestinal fluids at pH 5.5 and 6.8, respectively; and 75% in simulated colonic fluid at pH 7.4. CL-NBSCh showed considerably high selective cytotoxicity towards mucosal epithelial human colon cancer (HT-29) cells and lower levels of toxicity towards mouse connective tissue fibroblasts (L929). CL-NBSCh was also more cytotoxic than the free CL. Furthermore, compared to free CL, CL-NBSCh micelles were found to be more efficient at arresting cell growth at the G2/M phase, and induced apoptosis earlier in HT-29 cells. Collectively, these results indicate the high prospective potential of CL-loaded NBSCh micelles as an oral therapeutic intervention for colon cancer.

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The past, present, and future of chemotherapy with a focus on individualization of drug dosing

Cited by 12 publications

References 226 publications

The First-In-Class Anti-AXL×CD3ε Pronectin™-Based Bispecific T-Cell Engager Is Active in Preclinical Models of Human Soft Tissue and Bone Sarcomas

The First-In-Class Anti-AXL×CD3ε Pronectin™-Based Bispecific T-Cell Engager Is Active in Preclinical Models of Human Soft Tissue and Bone Sarcomas

Unveiling the mechanisms and challenges of cancer drug resistance

Development of pH-Responsive N-benzyl-N-O-succinyl Chitosan Micelles Loaded with a Curcumin Analog (Cyqualone) for Treatment of Colon Cancer

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