Abstract：
PURPOSE:Folate receptor (FR) targeted drug conjugates were prepared by covalently attaching the vitamin folate, to the potent anticancer drug, mitomycin C (MMC). One such conjugate, called EC72, was synthesized with an intramolecular disulfide bond, and it was found to exhibit efficacious anti-tumor activity against FR-expressing M109 tumors in a manner that yielded no gross or microscopic toxicity, even to FR-positive kidneys. METHODS:EC72's specificity was demonstrated by two methods: (1) blocking EC72's activity with an excess of co-administered folic acid (FA) in M109 tumor bearing mice and (2) the absence of therapeutic activity in mice bearing FR-negative tumors. The importance of having a cleavable bond in the conjugate was also exemplified, since EC110 (a folate-MMC conjugate constructed with a more resilient amide bond) failed to produce anti-M109 tumor activity. EC72's therapeutic potential was found to decrease with respect to the increasing size of subcutaneous tumor. However, a combination therapy with paclitaxel reproducibly improved the anti-tumor efficacy relative to either agent alone at well tolerated dose levels and with no apparent increase in toxicity. A more advanced folate-MMC conjugate was also synthesized in an effort to improve activity. Thus, EC118, a molecule constructed with both a reducible disulfide bond and an acid-labile hydrazone bond in the linker region, was tested and found to produce a significantly greater number of tumor regressions of more established M109 tumors than that achieved with EC72. CONCLUSION:Overall, these data indicate that folate-targeted drug therapy alone, or in combination with paclitaxel, may be a novel and effective clinical approach towards treating FR-positive cancers.
journal_name
Cancer Chemother Pharmacoljournal_title
Cancer chemotherapy and pharmacologyauthors
Reddy JA,Westrick E,Vlahov I,Howard SJ,Santhapuram HK,Leamon CPdoi
10.1007/s00280-005-0151-zkeywords:
subject
Has Abstractpub_date
2006-08-01 00:00:00pages
229-36issue
2eissn
0344-5704issn
1432-0843journal_volume
58pub_type
杂志文章abstract：PURPOSE:The sequence bendamustine (B) + Irinotecan (I) followed by etoposide (E) + carboplatin (C) was hypothesized to increase progression-free survival (PFS) and overall survival (OS) in untreated extensive-disease small cell lung cancer (EDSCLC) patients compared to historical controls by exploiting mitotic catastro...
journal_title：Cancer chemotherapy and pharmacology
pub_type： 杂志文章
doi：10.1007/s00280-015-2869-6
更新日期：2015-11-01 00:00:00
abstract：:Copovithane is an uncharged, water-soluble, synthetic polymer with an average molecular weight of 5800 daltons. It demonstrates antitumor activity in vivo against a variety of tumors in animal models but is inactive in vitro. This agent has been found to have immunorestorative activity in man. In concert with its phas...
journal_title：Cancer chemotherapy and pharmacology
pub_type： 杂志文章
doi：10.1007/BF00273396
更新日期：1986-01-01 00:00:00
abstract：:A major side effect of cisplatin treatment is peripheral neuropathy. In the past few years we have provided evidence that the ACTH4-9 analogue ORG 2766 provides protection against this neuropathy in rats and man. In this study we investigated the development of a cisplatin-induced neuropathy and the protective and the...
journal_title：Cancer chemotherapy and pharmacology
pub_type： 杂志文章
doi：10.1007/BF00685621
更新日期：1993-01-01 00:00:00
abstract：PURPOSE:2-Methoxyestradiol (2-ME) is a physiological metabolite of estrogen, which can inhibit growth of many types of tumor cells, including hepatocellular carcinoma, both in vitro and in vivo. The exact mechanisms of its action are still unclear. We have studied the mechanisms of growth inhibition of several of human...
journal_title：Cancer chemotherapy and pharmacology
pub_type： 杂志文章
doi：10.1007/s00280-007-0670-x
更新日期：2008-10-01 00:00:00
abstract：PURPOSE:RSR13, 2-[4-[2-[(3,5-dimethylphenyl)amino]-2-oxoethyl]phenoxy]-2-methylpropanoic acid monosodium salt, allosterically modifies hemoglobin to increase tumor pO(2), increases the effect of radiation in animal tumor models, and is in phase III clinical trials as an adjuvant to radiotherapy. Cisplatin and carboplat...
journal_title：Cancer chemotherapy and pharmacology
pub_type： 杂志文章
doi：10.1007/s00280-003-0715-8
更新日期：2004-01-01 00:00:00
abstract：PURPOSE:Chemotherapy dosing in neonates represents a major clinical challenge because of a lack of clinical pharmacology information in this patient population. In this study, we investigate the use of cisplatin dose adaptation based on therapeutic drug monitoring in a 2-week-old neonate with localized hepatoblastoma. ...
journal_title：Cancer chemotherapy and pharmacology
pub_type： 杂志文章
doi：10.1007/s00280-018-3625-5
更新日期：2018-08-01 00:00:00
abstract：PURPOSE:HER2-targeted therapy with trastuzumab and (CF/X) prolonged overall survival (OS) in metastatic HER2neu+ gastric carcinoma (GC). Lapatinib inhibits both EGFR and HER2neu. We investigated the efficacy and safety of lapatinib with epirubicin (E) + CF/X in GC according to HER2neu and EGFR status. METHODS:Tumors f...
journal_title：Cancer chemotherapy and pharmacology
pub_type： 杂志文章,多中心研究,随机对照试验
doi：10.1007/s00280-018-3667-8
更新日期：2018-10-01 00:00:00
abstract：PURPOSE:To investigate the efficacy and safety of combination chemotherapy with biweekly paclitaxel plus infusional 5-fluorouracil and leucovorin in the treatment of patients with advanced or metastatic gastric cancer. PATIENTS AND METHODS:Chemonaive patients with histologically confirmed advanced or recurrent inopera...
journal_title：Cancer chemotherapy and pharmacology
pub_type： 杂志文章
doi：10.1007/s00280-008-0752-4
更新日期：2009-02-01 00:00:00
abstract：:Dexniguldipine-HCl (DNIG)--a prospective clinical modulator of p170-glycoprotein (pgp170)-mediated multidrug resistance (MDR)--was evaluated in a drug-accumulation assay in MDR murine leukemia cell strain F4-6RADR expressing pgp170. The compound elevated low accumulation of either doxorubicin (DOX), daunorubicin (DNR)...
journal_title：Cancer chemotherapy and pharmacology
pub_type： 杂志文章
doi：10.1007/BF00685872
更新日期：1993-01-01 00:00:00
abstract：:The pharmacokinetics of hexamethylmelamine (HMM) and its first metabolite (hydroxymethylpentamethylmelamine: HMPMM) following IP bolus dose of 200 mg/kg were studied in mice. The drug concentrations were determined by a sensitive reversed-phase HPLC assay. Thus, for the first time, HMM major hydroxylated and demethyla...
journal_title：Cancer chemotherapy and pharmacology
pub_type： 杂志文章
doi：10.1007/BF00273391
更新日期：1986-01-01 00:00:00
abstract：PURPOSE:There is a need for effective chemotherapy protocols for gall bladder cancer (GBC). Gemcitabine has antitumor activity in pancreatic cancer. Oxaliplatin is effective in GI cancers. Based on evidence of synergy between these two, we designed this study to evaluate efficacy of this combination in unresectable GBC...
journal_title：Cancer chemotherapy and pharmacology
pub_type： 杂志文章
doi：10.1007/s00280-009-1055-0
更新日期：2010-02-01 00:00:00
abstract：BACKGROUND:The correlation of the oncological outcomes of docetaxel and cabazitaxel in Japanese metastatic castration-resistant prostate cancer (mCRPC) patients has not been unclear. MATERIALS AND METHODS:This study included a total of 47 consecutive Japanese mCRPC patients treated with cabazitaxel and assessed the pr...
journal_title：Cancer chemotherapy and pharmacology
pub_type： 杂志文章
doi：10.1007/s00280-018-3698-1
更新日期：2018-12-01 00:00:00
abstract：PURPOSE:To explore the clinical significance of plasma D-dimer increase for transcatheter arterial chemoembolization (TACE) in patients with primary liver cancer (PLC). METHODS:The clinical data of 80 PLC patients who underwent TACE in our hospital from January 2015 to January 2017 were collected, including the plasma...
journal_title：Cancer chemotherapy and pharmacology
pub_type： 杂志文章
doi：10.1007/s00280-019-03778-6
更新日期：2019-04-01 00:00:00
abstract：PURPOSE:In vitro and in vivo preclinical models have demonstrated synergistic activity when topoisomerase I and II inhibitors are administered sequentially. Topoisomerase I inhibitors increase topoisomerase II levels and increase cell kill induced by topoisomerase II poisons. We evaluated this hypothesis in a cohort of...
journal_title：Cancer chemotherapy and pharmacology
pub_type： 临床试验,杂志文章
doi：10.1007/s002800000211
更新日期：2001-01-01 00:00:00
abstract：OBJECTIVE:The aim of this study was to evaluate the efficacy and toxicities of liposome-paclitaxel and carboplatin concurrent with radiotherapy for locally advanced lung squamous cell carcinoma (LSCC). METHODS:The clinical data of 38 patients with locally advanced LSCC treated with liposome-paclitaxel based concurrent...
journal_title：Cancer chemotherapy and pharmacology
pub_type： 杂志文章
doi：10.1007/s00280-018-3640-6
更新日期：2018-09-01 00:00:00
abstract：:Previous studies have identified interleukin 6 (IL-6) as an important cytokine with prognostic significance in ovarian cancer. Activation of the IL-6-Stat3 pathway contributes to tumor cell growth, survival and drug resistance in several cancers, including ovarian cancer. To explore potential therapeutic strategies fo...
journal_title：Cancer chemotherapy and pharmacology
pub_type： 杂志文章
doi：10.1007/s00280-008-0785-8
更新日期：2009-03-01 00:00:00
abstract：:BS compounds, a series of new dihydropyridines, successfully overcame multidrug resistance in P388/ADR cells in vitro. These agents synergistically potentiated the cytotoxicity of Adriamycin to P388/ADR cells at a concentration of 1-2 microM, whereas they showed hardly any synergistic effect in the parental cell line ...
journal_title：Cancer chemotherapy and pharmacology
pub_type： 杂志文章
doi：10.1007/BF00257444
更新日期：1989-01-01 00:00:00
abstract：PURPOSE:A recirculating isolated perfused rat liver model was used to investigate the hepatobiliary disposition of etoposide and the effects of cyclosporine A (CyA) on the pattern of drug disposition in the bile and uptake in the liver. METHODS:The portal vein, bile duct, and superior vena cava were cannulated in four...
journal_title：Cancer chemotherapy and pharmacology
pub_type： 杂志文章
doi：10.1007/s00280-015-2719-6
更新日期：2015-05-01 00:00:00
abstract：PURPOSE:This study characterized the pharmacokinetics, mass balance, routes and extent of elimination, metabolites, and safety of a single oral dose of (14)C-linsitinib, an IGF-1R/IR inhibitor, in patients with advanced solid tumors. The tolerability of linsitinib after multiple-dose administration was assessed in thos...
journal_title：Cancer chemotherapy and pharmacology
pub_type： 杂志文章
doi：10.1007/s00280-016-2999-5
更新日期：2016-04-01 00:00:00
abstract：:A simple fluorescent microscopic method demonstrated that adriamycin was distributed in two cellular compartments of living rat colon cancer cells. Adriamycin accumulated slowly in cytoplasmic granules, probably lysosomes, where it persisted long after the drug was removed from the medium. On the other hand, adriamyci...
journal_title：Cancer chemotherapy and pharmacology
pub_type： 杂志文章
doi：10.1007/BF00401439
更新日期：1984-01-01 00:00:00
abstract：:The antimetabolite 1-beta-D-arabinofuranosyl-cytosine (ara-C) has proven to be one of the most effective agents available for the treatment of acute leukemia. While ara-C has been implicated as a potent inhibitor of mammalian cell DNA replication, the specific mechanism by which ara-C kills cells is not known. In this...
journal_title：Cancer chemotherapy and pharmacology
pub_type： 杂志文章
doi：10.1007/s002800050496
更新日期：1996-01-01 00:00:00
abstract：:CI-958, a new DNA-intercalating drug derived from a series of substituted 2H-[1] benzothiopyrano[4,3,2-cd]indazoles, is being tested in clinical trails because of its curative properties against murine solid tumor models and because it has demonstrated activity in a pilot phase II study of patients with hormone-refrac...
journal_title：Cancer chemotherapy and pharmacology
pub_type： 杂志文章
doi：10.1007/s002800050844
更新日期：1998-01-01 00:00:00
abstract：PURPOSE:Our aim was to develop an optimal sampling strategy for the description of the pharmacokinetics of rubitecan and its active metabolite 9-aminocamptothecin (9-AC) for use in phase II/III studies with oral rubitecan administered in a daily times five schedule. METHODS:Concentration-time data of rubitecan and 9-A...
journal_title：Cancer chemotherapy and pharmacology
pub_type： 临床试验,杂志文章,随机对照试验
doi：10.1007/s00280-002-0516-5
更新日期：2002-12-01 00:00:00
abstract：:Etoposide is a widely used cytotoxic drug that requires complex formulation for both the i.v. and oral preparation to ensure drug stability. Data on the stability of the i.v. formulation when diluted in infusion fluids are contradictory, and there is little information on the stability of the oral preparation in gastr...
journal_title：Cancer chemotherapy and pharmacology
pub_type： 杂志文章
doi：10.1007/BF00685638
更新日期：1995-01-01 00:00:00
abstract：PURPOSE:The histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA), enhances cisplatin [cis-diammine dichloroplatinum (II)] (CDDP)-induced apoptosis in the oral squamous cell carcinoma (OSCC) cell line by complex, multifunctional mechanisms. We investigated the role of endoplasmic reticulum (ER) stress i...
journal_title：Cancer chemotherapy and pharmacology
pub_type： 杂志文章
doi：10.1007/s00280-009-0969-x
更新日期：2009-11-01 00:00:00
abstract：:The cytotoxicity of cisplatin alone and in combination with topotecan (TPT) or SN-38, two novel topoisomerase I (topo I) inhibitors, was determined in a panel of eight well-characterized human solid-tumor cell lines. Interactions between cisplatin and these topo I inhibitors were investigated using three different adm...
journal_title：Cancer chemotherapy and pharmacology
pub_type： 杂志文章
doi：10.1007/s002800050744
更新日期：1998-01-01 00:00:00
abstract：:Mitoxantrone, 1,4-dihydroxy-5,8-bis(((2-[(2-hydroxyethyl)amino]ethyl) amino))-9,10-anthracenedione dihydrochloride, a new antitumor agent was evaluated in nine cancer patients as part of a phase I trial. In general, the drug was well tolerated. Leukopenia was the dose-limiting toxic effect. Mild to moderate leukopenia...
journal_title：Cancer chemotherapy and pharmacology
pub_type： 杂志文章
doi：10.1007/BF00578556
更新日期：1980-01-01 00:00:00
abstract：PURPOSE:Although treatment of melanoma with BRAF inhibitors and immune checkpoint inhibitors achieves a high response rate, a subset of melanoma patients with intrinsic and acquired resistance are insensitive to these therapeutics, so to improve melanoma therapy other target molecules need to be found. Here, we screene...
journal_title：Cancer chemotherapy and pharmacology
pub_type： 杂志文章
doi：10.1007/s00280-017-3317-6
更新日期：2017-06-01 00:00:00
abstract：PURPOSE:Fenretinide is a synthetic retinoid with activity in prostate cancer and other cell lines. The aim of this study was to assess the efficacy and tolerability of fenretinide in chemotherapy-naïve men with hormone refractory prostate cancer. METHODS:Eligibility criteria included hormone refractory prostate cancer...
journal_title：Cancer chemotherapy and pharmacology
pub_type： 杂志文章,多中心研究
doi：10.1007/s00280-009-1228-x
更新日期：2010-10-01 00:00:00
abstract：:The pharmacokinetics of mitomycin (MMC) was studied in Wistar rats. Up to five half-lives, the plasma concentration-time curve was biphasic. The AUC changed linearly with increasing doses between 0.5 and 7.5 mg/kg, which corresponds to 0.2 and 3 times the LD50 value in rats. Most of the drug was metabolized, and only ...
journal_title：Cancer chemotherapy and pharmacology
pub_type： 杂志文章
doi：10.1007/BF00257305
更新日期：1988-01-01 00:00:00
