Metabolism and ribonucleotide reductase inhibition of ( E   )-2′-deoxy-2′-(fluoromethylene)cytidine, MDL 101,731, in human cervical carcinoma HeLa S 3 cells

Takahashi, Takeshi; Nakashima, Akiko; Kanazawa, Junji; Yamaguchi, Kazuo; Akinaga, Shiro; Tamaoki, Tatsuya; Okabe, Masami

doi:10.1007/s002800050739

Cited by 21 publications

(17 citation statements)

References 14 publications

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“…In human tumors xenografted to animals it inhibits growth, and triggers apoptotic cell death of mammary, prostate, cervical and colorectal cancers, and gliomas (1,2,14,18,20,21,23).…”

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confidence: 99%

Effect of FMdC on the cell cycle of some leukemia cell lines

1999

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“…In human tumors xenografted to animals it inhibits growth, and triggers apoptotic cell death of mammary, prostate, cervical and colorectal cancers, and gliomas (1,2,14,18,20,21,23).…”

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confidence: 99%

Effect of FMdC on the cell cycle of some leukemia cell lines

1999

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“…Tezacitabine is also relatively resistant to metabolic deactivation from cytidine deaminase in other (cervical cancer) cell lines. 81 Four Phase I trials involving 70 patients with refractory solid tumours (including seven with pancreatic cancer) have shown objective antitumour activity in eight out of 70 patients (one partial response and seven with stable disease). 82 The recommended schedule for Phase II studies is one treatment every 2 weeks, at a minimum dose of 270 mg/m 2 .…”

Section: Cytosine Analoguesmentioning

confidence: 99%

Chemotherapy for pancreatic cancer

Shore

Raraty

Ghaneh

et al. 2003

Aliment Pharmacol Ther

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SUMMARYPancreatic cancer is a common, highly lethal disease that is rising in incidence. Chemotherapy based on 5-fluorouracil (5-FU) has been shown to prolong survival in advanced pancreatic cancer. Gemcitabine improves major symptoms and survival outcomes compared with bolus 5-FU. Many novel small molecules are being widely and actively researched. These compounds are based on classical mechanisms of action as well as biological therapies targeting novel cellular survival pathways, and include fluoropyrimidines, nucleoside cytidine analogues, platinum analogues, topoisomeraseinhibitors, antimicrotubule agents, proteasome inhibitors, vitamin D analogues, arachidonic acid pathway inhibitors, histone deacytylator inhibitors, farnesyltransferase inhibitors and epidermal growth factor receptor therapies.Adjuvant chemotherapy has also demonstrated the best survival outcomes following resection compared to other adjuvant or neo-adjuvant strategies such as radiation-based treatments. These benefits are superimposed on the dramatic increase in resectability rates and reduction in post-operative mortality achieved by centralisation of treatment in high-volume speciality centres. Newer 'small-molecule' drugs as well as the latest 'large-molecule' biological agents hold considerable promise for the future. Real advances are anticipated over the next five years but are dependent on large randomised controlled trials for success.

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“…7 Second, tezacitabine is approximately 30-fold more resistant than gemcitabine to metabolic inactivation through deamination by cytidine deaminase. 8 The latter could provide an advantage for tezacitabine in the treatment of cancer types in which cytidine deaminase levels are elevated or in individual patients who have tumors with high levels of the enzyme. For example, studies with human tumor xenografts suggest that many gastrointestinal tumors have high cytidine deaminase levels (unpublished data), and thus tezacitabine may be particularly useful in the treatment of this group of malignancies.…”

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confidence: 99%

“…These agents are potentially complementary because tezacitabine has been shown in in vitro studies to cause an accumulation of tumor cells in the S-phase of the cell cycle 6,9,10 and 5-FU has activity that is somewhat S-phase dependent. Combinations of tezacitabine with 5-FU and other S-phasespecific drugs have shown synergistic antiproliferative activity in vitro, 8 and studies with human and murine xenografts have shown synergistic and additive antitumor effects in vivo.…”

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confidence: 99%

Phase I dose‐escalation study of tezacitabine in combination with 5‐fluorouracil in patients with advanced solid tumors

Bendell

Eder

Clark

et al. 2005

Cancer

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BACKGROUNDTezacitabine [(E)‐2'‐deoxy‐2'‐(fluoromethylene) cytidine; FMdC] is a novel nucleoside analog with potent antiproliferative and antitumor activity in preclinical studies. A tolerable safety profile and clinical activity have been shown in Phase I and Phase II clinical studies. The purpose of the current open‐label, Phase I dose‐escalation trial was to evaluate the combination of tezacitabine and 5‐fluorouracil (5‐FU) in the treatment of patients with advanced solid tumors.METHODSTwenty‐four patients with a variety of advanced solid tumors for which there was no curative therapy were enrolled. Bolus infusion tezacitabine was administered on Day 1 of a 14‐day cycle at escalating doses of 150–350 mg/m2, with continuous infusion 5‐FU (CI 5‐FU) given on Days 1–7 at a fixed dose of 200 mg/m2 per day. Patients underwent objective tumor evaluation by radiologic methods or clinical examination at baseline and after every fourth treatment cycle.RESULTSThe maximum tolerated dose of the combination therapy was determined to be tezacitabine, 200 mg/m2, with CI 5‐FU, 200 mg/m2 per day. The toxicities were manageable, the most notable being transient severe (National Cancer Institute Common Toxicity Criteria Grade 3 or 4) neutropenia in 23 patients (96%). Eleven (55%) of the 20 assessable patients had partial responses or stabilization of disease. The highest response rate was in patients with primary tumors of esophageal origin.CONCLUSIONSTezacitabine at a dose of 200 mg/m2 in combination with CI 5‐FU at a dose of 200 mg/m2 per day was relatively well tolerated and had clinical activity in patients with advanced solid tumors, particularly in patients with esophageal and other gastrointestinal carcinomas. Cancer 2005. © 2005 American Cancer Society. Cancer 2005. © 2005 American Cancer Society.

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Metabolism and ribonucleotide reductase inhibition of ( E )-2′-deoxy-2′-(fluoromethylene)cytidine, MDL 101,731, in human cervical carcinoma HeLa S 3 cells

Abstract: This study suggests that the prolonged ribonucleotide reductase inhibition by rapidly activated metabolites of MDL 101,731 in part contributes to the potent antitumor activity of this drug against various xenografts.

Cited by 21 publications

References 14 publications

Effect of FMdC on the cell cycle of some leukemia cell lines

Effect of FMdC on the cell cycle of some leukemia cell lines

Chemotherapy for pancreatic cancer

Phase I dose‐escalation study of tezacitabine in combination with 5‐fluorouracil in patients with advanced solid tumors

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