Plant antitumor agents. 18. Synthesis and biological activity of camptothecin analogs

Wani, Mansukh C.; Ronman, Peter; Lindley, James T.; Wall, Monroe E.

doi:10.1021/jm00179a016

Cited by 223 publications

(119 citation statements)

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“…The anti-cancer activity of natural macrocyclic lactones (1,2) and delta-lactones isolated from plants or fungi (3,4) have been reported. We extensively studied the activity of their synthesized compounds and previously reported the activity of the low-molecular-weight delta-alkyllactones and macrocyclic lactones (5,6).…”

Section: Introductionmentioning

confidence: 99%

Antitumor and anti-invasive effects of diverse musk-fragrant macrocyclic ketones and their enhancement by hyperthermia

Kageyama

2011

Mol Med Report

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Abstract. The antitumor and anti-invasive activities of the low-molecular-weight macrocyclic ketones (MCKs), such as musk secreted from the mammalian genital glands and musk released from relatively unkown plants, were investigated comparatively together with the enhancement of the effects in combination with hyperthermia. Ehrlich ascites tumor cells were treated with each MCK and cultured, followed by evaluation of the cell viability using the mitochondrial dehydrogenase-based WST-8 assay. The number of HT-1080 human fibrosarcoma cells cultured with the MCKs or invading through a reconstituted basement membrane was measured using microscopy. The order of the efficiency was as follows: (Z)-g-cycloheptadecen-1-one (Hp) (17:1, musk rats), 8-cyclohexadecen-1-one (16:1, musk ferns), cyclopentadecanone (15:0, musk rats) and 3-methylcyclopentadecanone (16:0, musk deer), having 15-17 carbon atoms with and without a double bond, which exhibited a carcinostatic effect either at 100 µM for 20-h culture or at 50 µM for 72-h culture. The effects were markedly enhanced by heat treatment at 42˚C. MCKs were not found in the cells by gas-liquid chromatographic determination, indicating that the carcinostatic effects were attributed to their surface activity on the cell membrane. Invasion of HT-1080 cells was inhibited by MCKs at doses scarcely diminishing the cell viability, indicating that the suppression of invasiveness did not ensue from the secondary action due to carcinostasis. The order of invasion-inhibitory efficacy of the MCKs was, however, similar to that of their carcinostatic effects. Hp17:1 also exhibited the highest anti-invasive activity in addition to the highest carcinostatic activity. The two inhibitory effects were promoted by combination with hyperthermia. MCKs with a double bond, particularly Hp17:1 rather than 8-Hx16:1, but not saturated-aliphatic MCKs, may be potent multi-applicable antitumor agents due to their dual inhibitory activities against tumor progression and invasion and in hyperthermia-combined therapy. IntroductionThe anti-cancer activity of natural macrocyclic lactones (1,2) and delta-lactones isolated from plants or fungi (3,4) have been reported. We extensively studied the activity of their synthesized compounds and previously reported the activity of the low-molecular-weight delta-alkyllactones and macrocyclic lactones (5,6).However, there have been few reports to date regarding the activities of MCKs similar to the lactone compounds (7,8). These compounds have the highest molecular weights (approximately 1,060 Da) of the MCKs. With regard to the low-molecular-weight (224-250 Da) MCKs contained in musks secreted from the mammalian genital gland, these MCKs are quite chemically different from conventional substances. Their anti-tumor activity has yet to be elucidated.In the present study, the carcinostatic activity of the MCKs was studied using Ehrlich ascites tumor (EAT) cells. The carcinostatic effects were evaluated by a decrease in mitochondrial dehydrogenase activity reflecting the sur...

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Section: Introductionmentioning

confidence: 99%

Antitumor and anti-invasive effects of diverse musk-fragrant macrocyclic ketones and their enhancement by hyperthermia

Kageyama

2011

Mol Med Report

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“…CPT has significant antitumor efficacy across a broad spectrum of human tumor xenograft models (2,7,8). Although antitumor activity was evident in phase I trials with the sodium salt of CPT, which was used to overcome the insolubility of the lactone form of CPT, only modest response rates and severe toxicities were observed in phase II trials (9,10).…”

Section: Introductionmentioning

confidence: 99%

“…1 Division of Pharmacotherapy & Experimental Therapeutics, UNC Eshelman School of Pharmacy, 2 Translational Oncology and Nanoparticle Drug Development (TOND 2 I) Lab, 3 Molecular Therapeutics, UNC Lineberger Comprehensive Cancer Center, 4 UNC GLP Bioanalytical Lab, 5 UNC Institute for Pharmacogenomics and Individualized Therapy (IPIT), 6 Carolina Center for Cancer Nanotechnology Excellence (C-CCNE), 7 North Carolina Biomedical Innovation Network, University of North Carolina, Chapel Hill, North Carolina; and 8 Mersana Therapeutics, Inc., Cambridge, Massachusetts commonly associated with severe neutropenia. Irinotecan treatment often causes both neutropenia and acute or delayed diarrhea, which can be life threatening in patient populations with genetic polymorphisms that reduce glucuronidation of active irinotecan metabolite SN-38 to SN-38-G.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics and Antitumor Efficacy of XMT-1001, a Novel, Polymeric Topoisomerase I Inhibitor, in Mice Bearing HT-29 Human Colon Carcinoma Xenografts

Walsh

Hanna

Sen

et al. 2012

Clinical Cancer Research

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Purpose: To evaluate the pharmacokinetics and tissue disposition of macromolecular camptothecin (CPT) drug conjugate, XMT-1001, and irinotecan (CPT-11) in mice bearing HT-29 xenograft tumors. Experimental Design: The antitumor efficacy of XMT-1001 was evaluated in the mouse HT-29 human colon carcinoma xenograft model. XMT-1001 was administered intravenously to female athymic nude (nu/nu) mice bearing established HT-29 xenograft tumors (n = 10) at 15, 30, and 60 mg CPT equivalents/kg on weekly or biweekly schedules. The tumor growth inhibition and tumor growth delay endpoints were used for efficacy evaluation. In the pharmacokinetic study, XMT-1001 was administered intravenously at a pharmacologically relevant dose of 60 mg CPT equivalents/kg × 1 via tail vein or an equimolar dose of CPT-11 at 100 mg/kg i.p. × 1. Mice (n = 3 per time point) were euthanized from 0.083 to 336 hours after XMT-1001 administration and from 0.083 to 24 hours after CPT-11. Plasma, tumor, and tissues were collected from all animals. A liquid chromatography–tandem mass spectrometry assay was used to measure XMT-1001, conjugate release products, CPT-20-O-(N-succinimido-glycinate; CPT-SI) and CPT-20-O-(N-succinamidoyl-glycinate; CPT-SA), and CPT. Results: After XMT-1001 administration, the majority of the plasma exposure is accounted for by conjugated CPT. XMT-1001 exhibited a prolonged exposure of conjugated drug, active conjugate primary release products, CPT-SI and CPT-SA, and active CPT, which was associated with greater antitumor response compared with CPT-11. Conclusions: XMT-1001 provides an extended systemic and tumor exposure of conjugated drug and shows improved antitumor effect compared with CPT-11. Clin Cancer Res; 18(9); 2591–602. ©2012 AACR.

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“…Camptothecin exists in two forms, the lactone form and the 10-fold less active carboxylate form (3,4). Native camptothecin showed antitumor activity in animal models (5) and in phase 1 clinical trials (6,7) in the 1960s and 1970s, with myelosuppression being the dose-limiting toxicity (DLT).…”

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confidence: 99%

Phase 1 Study of Weekly Polyethylene Glycol-Camptothecin in Patients with Advanced Solid Tumors and Lymphomas

Posey

Saif

Carlisle

et al. 2005

Clinical Cancer Research

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Purpose:To determine the maximal tolerated dose and dose-limiting toxicities (DLT) of pegamotecan (polyethylene glycol-camptothecin) in patients with advanced malignancies when administered in cycles of once weekly for 3 of 4 weeks. Experimental Design: Eligible patients had advanced solid tumors that failed to respond to standard therapy or for which no standard therapy was available, including also the following criteria: measurable disease, Eastern Cooperative Oncology Group performance status of V2, and acceptable organ function. Pegamotecan was administered as a 60-minute infusion, with successive patient cohorts receiving escalating doses from 800 to 4,300 mg/m 2 . The primary end point was to determine the maximal tolerated dose. Other end points were toxicity, pharmacokinetics, pharmacodynamics, and efficacy. Pharmacokinetic analysis measured free camptothecin. Pharmacodynamic analysis correlated drug effects with pegamotecan dose and pharmacokinetic variables. Results: Twenty-seven patients were enrolled. The maximal tolerated dose was 3,240 mg/m 2 . Grade 4 neutropenia, the DLT, was noted in two of four patients treated at 4,300 mg/m 2 . Other grade 3 and 4 toxicities were anemia, thrombocytopenia, fatigue, prolonged partial thromboplastin time, hemorrhagic cystitis, dysuria, and urinary frequency. Pharmacokinetic analysis showed the apparent terminal elimination half-life to be 46 F 12.8 hours. Pharmacodynamic analysis showed that hematuria occurred in 8 of 15 patients with an area under the curve extrapolated to infinity (AUC 0-1 ) > 20 ng h/mL and 0 of10 patients with an AUC 0-1 V 20 ng h/mL. Unconfirmed partial responses were observed in two patients, one with metastatic small bowel adenocarcinoma and the other with metastatic esophageal cancer. Conclusions: The maximal tolerated dose of pegamotecan when administered weekly for 3 of 4 weeks is 3,240 mg/m 2 . The DLT was neutropenia. Among nonhematologic toxicities, the incidence of gastrointestinal toxicity was low, but genitourinary toxicity seems to occur in the same effective dose range as noted with native camptothecin in earlier trials (27-43 mg/m 2 ). The observed antitumor activity suggests that pegamotecan has single-agent activity and merits further investigation in phase 2 studies.

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Plant antitumor agents. 18. Synthesis and biological activity of camptothecin analogs

Cited by 223 publications

References 3 publications

Antitumor and anti-invasive effects of diverse musk-fragrant macrocyclic ketones and their enhancement by hyperthermia

Antitumor and anti-invasive effects of diverse musk-fragrant macrocyclic ketones and their enhancement by hyperthermia

Pharmacokinetics and Antitumor Efficacy of XMT-1001, a Novel, Polymeric Topoisomerase I Inhibitor, in Mice Bearing HT-29 Human Colon Carcinoma Xenografts

Phase 1 Study of Weekly Polyethylene Glycol-Camptothecin in Patients with Advanced Solid Tumors and Lymphomas

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