Gemcitabine CAS 95058-81-4

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Gemcitabine CAS 95058-81-4, also known as difluorodeoxycytidine, is a pyrimidine nucleoside analog and a widely used antineoplastic agent. Its chemical formula is C₉H₁₁F₂N₃O₄, and as a member of the cytarabine family, it exerts its antitumor effects through a well‑characterized intracellular activation and metabolic pathway. Within the body, gemcitabine is initially phosphorylated and activated by deoxycytidine kinase, while its inactivation and clearance are primarily mediated by cytidine deaminase. The primary mechanism of action involves its active metabolites being incorporated into replicating DNA strands, predominantly targeting cells in the G1/S phase of the cell cycle and inducing chain termination and DNA damage. Notably, gemcitabine exhibits a unique self‑potentiating effect that distinguishes it from cytarabine: in addition to direct DNA incorporation, it also inhibits ribonucleotide reductase, which reduces intracellular levels of deoxynucleotide triphosphates and further favors its own incorporation into DNA. It also inhibits cytidine deaminase, thereby decreasing the metabolic degradation of its active intracellular metabolites and prolonging their cytotoxic activity. This dual inhibitory action enhances its overall antitumor potency and contributes to its broad clinical utility in various solid tumors and hematologic malignancies.

► Cellular Uptake

Gemcitabine enters neoplasm cells primarily through nucleoside transporters located on the cell membrane. The two main types of transporters involved are the human equilibrative nucleoside transporter 1 (hENT1) and the human concentrative nucleoside transporter 1 (hCNT1). The expression levels of these transporters can vary among different neoplasm types and individual tumors, which may influence the sensitivity of neoplasm cells to gemcitabine. Once inside the cell, gemcitabine is ready for further metabolic activation.

► Phosphorylation Cascade

First Phosphorylation Step: The initial phosphorylation of gemcitabine to gemcitabine monophosphate (dFdCMP) is catalyzed by deoxycytidine kinase (dCK). dCK is a key enzyme in the activation of gemcitabine, and its activity can be regulated by various factors, including the availability of substrates and the presence of inhibitors.

Subsequent Phosphorylation: dFdCMP is then further phosphorylated to gemcitabine diphosphate (dFdCDP) by nucleoside monophosphate kinases and then to the active triphosphate form, gemcitabine triphosphate (dFdCTP), by nucleoside diphosphate kinases. dFdCTP is the most biologically active metabolite and is responsible for the majority of gemcitabine's cytotoxic effects.

► DNA - Related Mechanisms

Masked Chain Termination: dFdCTP can be incorporated into DNA during DNA replication by DNA polymerases. Once incorporated, an additional nucleotide can be added to the growing DNA strand. However, the presence of the two fluorine atoms on the deoxyribose ring of gemcitabine causes a conformational change in the DNA structure. This change makes it difficult for the DNA polymerase to continue adding nucleotides, effectively terminating DNA synthesis. The incorporated gemcitabine is "masked" in the DNA, protecting it from immediate excision by DNA repair enzymes, which allows the cytotoxic effect to persist.

Inhibition of Ribonucleotide Reductase: dFdCDP also plays a crucial role in gemcitabine's mechanism of action. It inhibits ribonucleotide reductase, an enzyme that converts ribonucleotides to deoxyribonucleotides. Deoxyribonucleotides are essential building blocks for DNA synthesis. By inhibiting ribonucleotide reductase, dFdCDP reduces the pool of available deoxyribonucleotides, further limiting DNA synthesis in neoplasm cells. This dual mechanism of action, targeting both DNA synthesis directly and the supply of deoxyribonucleotides, makes gemcitabine a highly effective anti - neoplasm drug.

Clinically, gemcitabine displays a distinct antitumor spectrum from cytarabine, demonstrating efficacy against various solid tumors. It is administered as an intravenous injection and is used as a metabolic anticancer drug. Approved indications include its use in neoplasm treatment, particularly for non-small cell lung neoplasm, pancreatic neoplasm, breast neoplasm, and bladder neoplasm, among others. It inhibits DNA synthesis and repair, ultimately leading to autophagy and apoptosis of cancer cells.

1. Indications

It is indicated for the treatment of several types of neoplasm, including but not limited to:

• Pancreatic neoplasm: Commonly used as a first-line or second-line therapy for advanced or metastatic pancreatic cancer, either alone or in combination with other chemotherapeutic agents.
• Non-Small Cell Lung neoplasm(NSCLC): It is an effective treatment option for locally advanced or metastatic NSCLC, either as monotherapy or in combination regimens.
• Breast neoplasm: In combination with other drugs like paclitaxel, is utilized in the treatment of recurrent or metastatic breast cancer.
• Bladder neoplasm: It has been approved for use in certain bladder cancer settings, offering an alternative treatment option for patients.
• Other Solid Tumors: Also shown efficacy in the treatment of ovarian neoplasm, cervical neoplasm, and prostate neoplasm, among others, though its use in these indications may be more limited or investigational.

2. Combination Therapy

It is often administered in combination with other chemotherapeutic agents to enhance efficacy and manage side effects. Some common combination regimens include:

•  + Cisplatin: Used in the treatment of NSCLC, pancreatic neoplasm, and other solid tumors.
•  + Paclitaxel: A popular combination for metastatic breast neoplasm.
•  + Carboplatin: An alternative regimen for NSCLC and other neoplasm.
•  + Fluorouracil (5-FU): Utilized in certain pancreatic neoplasm and renal neoplasm treatment protocols.

3. Dosage and Administration

It is administered intravenously, with the specific dosage and administration schedule tailored to the patient's condition and the intended treatment regimen. Common dosing schedules include weekly administrations for 3 consecutive weeks followed by a week of rest, or biweekly administrations depending on the combination therapy and patient tolerance.

4. Mechanism of Action

The mechanism of action involves its incorporation into DNA, primarily during the S-phase of the cell cycle, leading to inhibition of DNA synthesis and repair. Additionally, it inhibits ribonucleotide reductase, resulting in decreased levels of deoxynucleotide triphosphates (dNTPs) within the cell, further impairing DNA synthesis. These effects ultimately lead to cell death through apoptosis and autophagy.

5. Side Effects and Precautions

While it is an effective anticancer agent, it is associated with several side effects that patients and healthcare providers should be aware of. These include but are not limited to:

Bone Marrow Suppression: Can cause anemia, neutropenia, and thrombocytopenia, requiring regular blood monitoring.

Gastrointestinal Toxicity: Nausea, vomiting, and diarrhea are common, often manageable with supportive care.

Hepatic and Renal Impairment: Patients with pre-existing liver or kidney dysfunction may require dose adjustments.

Neurotoxicity: Peripheral neuropathy and fatigue can occur, impacting patients' quality of life.

Pulmonary Toxicity: Rarely, patients may experience dyspnea or acute respiratory distress syndrome.

To mitigate these side effects and ensure safe and effective treatment, patients should be closely monitored during therapy, and dose adjustments or treatment interruptions may be necessary based on individual patient tolerance and response.

In conclusion, gemcitabine is a valuable addition to the oncologist's toolbox, offering a potent and versatile treatment option for a wide range of solid tumors. Its clinical applications continue to evolve as researchers explore new combination therapies and indications, further expanding its role in neoplasm care.

• Pharmaceutical Companies: Eli Lilly and Company continues to be the primary developer and manufacturer, but collaborations and partnerships with other pharmaceutical companies have also contributed to its development and commercialization.
• Academic Institutions: Research institutions and universities have also played a role in advancing the understanding of its mechanism of action and in developing new therapeutic strategies using this drug.
  

   

   

  Gemcitabine has firmly established itself as a key player in neoplasm chemotherapy, with a wide range of clinical applications in the treatment of various solid tumors. Its unique mechanism of action, relatively manageable side - effect profile, and potential for combination with other therapies make it a valuable drug in the oncologist's arsenal. Ongoing research in combination therapies, drug delivery systems, and biomarker identification holds great promise for further enhancing the effectiveness of gemcitabine and improving the quality of life and survival of neoplasm patients.

   

As our understanding of neoplasm biology and pharmacology continues to advance, gemcitabine is likely to remain an important component of neoplasm  treatment for the foreseeable future.In summary, gemcitabine has a rich development history that spans from its initial synthesis and clinical evaluation to its widespread use in the treatment of various neoplasm types. Its efficacy and tolerability have made it a valuable addition to the oncologist's armamentarium, and ongoing research continues to explore new ways to improve its use in neoplasm therapy.

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