Tezacitabine CAS No. 130306-02-4

Product Description

Warning: This product is for research use only and is not for clinical use.

Tezacitabine (FMdC, NSC 286193) is a synthetic pyrimidine nucleoside analogue designed to mimic cytidine; after cellular phosphorylation it produces a diphosphate metabolite that irreversibly inhibits ribonucleotide reductase (RNR) and a triphosphate form that is incorporated into DNA, acting as a chain terminator and inducing apoptosis, especially in rapidly dividing tumor cells. Originally advanced for leukemia, myelodysplastic syndromes and several solid tumors, the agent demonstrated promising pre-clinical activity but encountered dose-limiting toxicities—severe and prolonged myelosuppression with febrile neutropenia—during early-phase trials. These safety concerns, coupled with limited therapeutic efficacy, led sponsors to halt development.

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Product Use & Characteristics

Structural & Physicochemical Data

• IUPAC Name: 4-amino-1-[(2R,3E,4S,5R)-3-(fluoromethylidene)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one

• Molecular Formula / MW: C₁₀H₁₂FN₃O₄ / 257.22 g·mol⁻¹

• Chemical Class: Fluorinated pyrimidine nucleoside analogue (cytidine derivative)

Mechanism of Action

• Dual pathway:

  FMdCDP → irreversible inhibition of ribonucleotide reductase (RNR) → ↓ dNTP pools.

  FMdCTP → incorporation into DNA → chain termination & apoptosis.

• Additional effects: radiosensitization, anti-angiogenesis, up-regulation of thymidine phosphorylase (TP).

Resistance & Metabolic Profile

• Resistant to cytidine deaminase deactivation → longer intracellular half-life compared with gemcitabine.

Pre-clinical Activity

• In vitro: IC₅₀ 10–90 nM in lung, colon, breast, prostate, pancreas, ovary, brain, leukemia & multidrug-resistant lines.

• In vivo: murine tumors & human xenografts (breast, prostate, lung, colon, intracerebral glioma).

• Synergy demonstrated with cisplatin, ara-C, 5-FU, FUdR, capecitabine, radiation ± pentoxifylline.

Clinical Development Summary

• Indications studied: refractory solid tumors (colorectal, breast, pancreatic, NSCLC, gastric, cholangiocarcinoma).

• Phase I trials: 70 patients across 4 schedules (q3-weekly → twice-weekly).

• Recommended Phase II dose: 270 mg/m² every 2 weeks (based on neutropenia recovery).

• PK profile: linear, t½ 3–4 h; 23 % unchanged drug in urine, 63 % as metabolite FMdU; no accumulation.

Toxicity (Phase I)

• Dose-limiting toxicity (DLT): Grade 3–4 neutropenia (53 % of patients).

• Other: transient infusion-related fever (82 %), mild GI symptoms, rare thrombocytopenia; no drug-related deaths.

Uses / Applications

• Anticancer (investigational):

  Single-agent or combination therapy for leukemias & solid tumors.

  Sequential FMdC → FUdR → potentiated DNA-directed cytotoxicity & apoptosis (colon cancer models).

  FMdC + capecitabine → additive tumor growth inhibition (HCT-116 xenografts) via TP up-regulation.

• Abandoned: antiviral (HIV) insufficient advancement.

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