Human and murine macrophages mediate activation of MEN 4901/T-0128: a new promising camptothecin analogue–polysaccharide conjugate

Binaschi, Monica; Parlani, Massimo; Bellarosa, Daniela; Bigioni, Mario; Salvatore, Carmela; Palma, Carla; Crea, Attilio; Maggi, Carlo Alberto; Manzini, Stefano; Goso, Cristina

doi:10.1097/01.cad.0000236307.20339.b4

Cited by 8 publications

(18 citation statements)

References 16 publications

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“…The liver, spleen and lymph nodes, however, also showed significant uptake, suggesting recognition by the reticuloendothelial system, which was later investigated and confirmed in studies involving macrophage-mediated activation of T-0128. 289, 290 …”

Section: Macromolecular Architectures For Passive Drug Deliverymentioning

confidence: 99%

Cancer Therapies Utilizing the Camptothecins: A Review of the in Vivo Literature

2010

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This review summarizes the in vivo assessment--preliminary, preclinical, and clinical--of chemotherapeutics derived from camptothecin or a derivative. Camptothecin is a naturally occurring, pentacyclic quinoline alkaloid that possesses high cytotoxic activity in a variety of cell lines. Major limitations of the drug, including poor solubility and inactivity at physiological conditions, prevent full clinical utilization. Camptothecin remains at equilibrium in an active lactone form and inactive hydrolyzed carboxylate form. The active lactone binds to DNA topoisomerase I cleavage complex, believed to be the single site of activity inhibiting DNA religation, resulting in apoptosis. A series of small molecule camptothecin derivatives have been developed that increase solubility, lactone stability and bioavailability to varying levels of success. A number of macromolecular agents have also been described wherein camptothecin(s) are covalently appended or non-covalently associated with the goal of improving solubility and lactone stability, while taking advantage of the tumor physiology to deliver larger doses of drug to the tumor with lower systemic toxicity. With the increasing interest in drug delivery and polymer therapeutics, additional constructs are anticipated. The goal of this review is to summarize the relevant literature for others interested in the field of camptothecin-based therapeutics, specifically in the context of biodistribution, dosing regimens, and pharmacokinetics with the desire of providing a useful source of comparative data. To this end, only constructs where in vivo data is available are reported. The review includes published reports in English through mid-2009.

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Section: Macromolecular Architectures For Passive Drug Deliverymentioning

confidence: 99%

Cancer Therapies Utilizing the Camptothecins: A Review of the in Vivo Literature

2010

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“…Figure 6 shows that in the culture medium T‐2513 is present at a concentration able to kill A2780 cells. T‐2513 release from delimotecan depends on Cathepsin B activity 11. The activity of this enzyme into Me 15392 cells is at least 5–6‐fold higher than that present in differentiated THP‐1+PMA monocytic cells.…”

Section: Resultsmentioning

confidence: 99%

“…Because macrophages are cells specialized in phagocytose activity and they are able to phagocytose delimotecan,10, 11 we evaluated the percentage of macrophage cells recruited into the tumor tissue. Figure 7 Panels a – d , shows that in the tumor nodule generated by Me 15392, there is a significant amount of macrophages evaluated by FACS analysis with F4/80 staining (27%) a macrophage‐restricted receptor.…”

Section: Resultsmentioning

confidence: 99%

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Antitumor activity of delimotecan against human metastatic melanoma: Pharmacokinetics and molecular determinants

Bigioni

Parlani

Bressan

et al. 2009

Intl Journal of Cancer

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Delimotecan (MEN 4901/T-0128) is a new cytotoxic prodrug constituted by a camptothecin analog (T-2513) bound to carboxymethyl dextran through a triglycine linker. A significant antitumor activity of delimotecan against human metastatic melanoma xenograft model Me15392 is reported. Dacarbazine, the drug approved for the treatment of metastatic melanoma, was ineffective in this melanoma model. Pharmacokinetic studies, together with the expression analysis of mRNA for enzymes involved in delimotecan metabolism, showed that T-2513 and other cytotoxic metabolites of delimotecan (SN 38 and T-0055) are generated in greater quantities in the tumor tissue than in toxicity target tissues, such as liver, thus accounting for the antitumoral activity. Moreover, we demonstrated that human metastatic melanoma cells are able to phagocytose delimotecan and cleave it to release the cytotoxic moieties T-2513 in the tumoral environment. Further flow cytometric analysis showed a higher recruitment of macrophages in xenografted human metastatic melanoma, when compared with other human tumors. Thus, the antitumoral activity of delimotecan exerted on metastatic melanoma is due to several factors: (i) the ability of melanoma cells to phagocytose and metabolise delimotecan; (ii) the accumulation of delimotecan in tumoral mass; (iii) the recruitment of macrophage cells to the melanoma nodule and (iv) the expression in melanoma cells of a pattern of enzymes that converts delimotecan into cytotoxic metabolites. Based on these results, delimotecan might be exploited as a new anticancer agent for the therapy of metastatic melanoma because of its high efficacy and good selectivity, and therefore clinical trials for this indication are warranted. ' UICCKey words: delimotecan; Cathepsin B; metastatic melanoma; macrophages In the last 5 decades, a steady increase in the incidence of malignant melanoma has been observed. The majority of patients diagnosed with early-stage malignant melanoma are cured by primary surgical treatment, but individuals with deeply invasive melanoma have a high probability of developing distant metastases.

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“…Preclinical studies suggested that delimotecan can permeate and accumulate in tumor tissue and is cleaved to T-2513 by cathepsin B, which is overexpressed in tumors. These studies further showed that tumor-associated macrophages may play a key role in the uptake of delimotecan and cleavage and local release of T-2513 (12,13). T-2513 can be metabolized to the CPT analogues, T-0055, T-1335, T-3921, and SN-38 (the active metabolite of CPT-11), which is glucuronidated to SN-38 glucuronide (SN-38G; Fig.…”

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Clinical and Pharmacologic Study of the Novel Prodrug Delimotecan (MEN 4901/T-0128) in Patients with Solid Tumors

Veltkamp

Witteveen

Capriati

et al. 2008

Clinical Cancer Research

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Purpose: To investigate i.v. administration of delimotecan (MEN 4901/T-0128), a carboxymethyldextran polymer prodrug of the active camptothecin derivative T-2513, and to assess the maximum tolerated dose, safety profile, clinical pharmacology, and antitumor activity of delimotecan and metabolites. Experimental Design: Patients with solid tumors refractory to standard therapy received i.v. delimotecan as 3-hour infusion once every 6 weeks. The starting dose was 150 mg/m 2 , followed by an accelerated dose escalation with at least one patient per dose level.The pharmacokinetics of delimotecan, T-2513, and its metabolites, SN-38, SN-38G, T-1335, T-0055, and T-3921, were assessed in plasma and urine, and their pharmacodynamics were determined by measuring the effect of the treatment on hematologic and nonhematologic toxicity. Results: Twenty-two patients received 35 courses. Dose-limiting toxicities were observed at 5,400 mg/m 2 (n = 1), 3,600 mg/m 2 (n = 1), and 2,400 mg/m 2 (n = 2). The dose level of 1,800 mg/m 2 was determined as maximum tolerated dose. Two partial responses were observed in patients with anal cancer (1800 mg/m 2 ) and head and neck cancer (2400 mg/m 2 ). Delimotecan had a long terminal half-life of 109 h, and relatively high exposures to T-2513 and SN-38 were obtained. The percentage decrease in WBC and absolute neutrophil count significantly correlated with the dose of delimotecan. Conclusions: Based on its preliminary antitumor activity, safety profile, and pharmacokinetic profile, we recommend to evaluate delimotecan given as 3-hour infusion once every 6 weeks at a dose level of 1,800 mg/m 2 in a phase II study.

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Human and murine macrophages mediate activation of MEN 4901/T-0128: a new promising camptothecin analogue–polysaccharide conjugate

Cited by 8 publications

References 16 publications

Cancer Therapies Utilizing the Camptothecins: A Review of the in Vivo Literature

Cancer Therapies Utilizing the Camptothecins: A Review of the in Vivo Literature

Antitumor activity of delimotecan against human metastatic melanoma: Pharmacokinetics and molecular determinants

Clinical and Pharmacologic Study of the Novel Prodrug Delimotecan (MEN 4901/T-0128) in Patients with Solid Tumors

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