Oxaliplatin

Synthetic Routes and Reaction Conditions: Oxaliplatin is synthesized through a multi-step process involving the reaction of platinum compounds with specific ligands. The primary synthetic route involves the reaction of cis-diiodo(trans-1,2-diaminocyclohexane)platinum(II) with oxalic acid. The reaction conditions typically include a controlled temperature and pH to ensure the formation of the desired product .

Industrial Production Methods: In industrial settings, this compound is produced using large-scale reactors where the reaction conditions are meticulously controlled to achieve high yields and purity. The process involves the use of high-purity starting materials and solvents, and the final product is subjected to rigorous quality control measures to ensure its efficacy and safety .

Arten von Reaktionen: Oxaliplatin durchläuft verschiedene Arten von chemischen Reaktionen, darunter Substitution, Oxidation und Reduktion. Die bemerkenswerteste Reaktion ist seine Fähigkeit, kovalente Bindungen mit DNA zu bilden, was zur Bildung von Intrastrang- und Interstrang-Quervernetzungen führt .

Häufige Reagenzien und Bedingungen: Die Reaktionen, an denen this compound beteiligt ist, erfordern oft spezifische Reagenzien wie Chloridionen, Wasser und verschiedene organische Lösungsmittel. Die Bedingungen umfassen typischerweise kontrollierte Temperaturen und pH-Werte, um die gewünschten chemischen Umwandlungen zu ermöglichen .

Hauptprodukte, die gebildet werden: Die Hauptprodukte, die aus den Reaktionen von this compound entstehen, sind DNA-Addukte, die für seine zytotoxischen Wirkungen verantwortlich sind. Diese Addukte verhindern die DNA-Replikation und -Transkription, was zum Zelltod führt .

Colorectal Cancer

Indications:

• Oxaliplatin is primarily indicated for:
  • Stage III colorectal cancer : Used as adjuvant therapy post-surgery.
  • Metastatic colorectal cancer : Often combined with 5-fluorouracil and leucovorin in the FOLFOX regimen .

Efficacy:

• A phase II trial reported a response rate of 24.3% in patients with previously untreated metastatic colorectal adenocarcinoma, with a median progression-free survival of 126 days .
• Combination therapies have shown improved response rates ranging from 34% to 67% , significantly enhancing survival outcomes compared to treatments without this compound .

Off-Label Uses

This compound has also been explored for off-label indications, including:

• Refractory or relapsed solid tumors in pediatric patients.
• Refractory neuroendocrine tumors and various hematologic malignancies .
• Advanced ovarian cancer and refractory testicular cancer , often in combination with other agents like gemcitabine and paclitaxel .

Kounis Syndrome Induced by this compound

A notable case study documented a 52-year-old woman who experienced Kounis syndrome—a hypersensitivity reaction affecting cardiac tissue—after administration of this compound. This case highlighted the need for awareness regarding hypersensitivity reactions to platinum-based drugs .

Extravasation Events

Another case reported significant tissue damage following the extravasation of this compound during an infusion. Despite the severity of the incident, the patient showed remarkable recovery without surgical intervention after appropriate management .

Side Effects and Toxicity Profile

While this compound is effective, it is associated with several adverse effects:

• Peripheral sensory neuropathy : One of the most common side effects, reported in up to 40% of patients.
• Other toxicities include gastrointestinal disturbances (nausea, vomiting), hematologic issues (neutropenia), and acute dysesthesias .

Comparative Efficacy

The following table summarizes key findings from various clinical trials regarding this compound's efficacy:

Oxaliplatin exerts its effects by forming covalent bonds with DNA, leading to the formation of DNA cross-links. These cross-links prevent DNA replication and transcription, ultimately causing cell death. The primary molecular targets of this compound are the purine bases in DNA, where it forms intrastrand and interstrand cross-links .

The pathways involved in the mechanism of action of this compound include the activation of DNA damage response pathways, leading to cell cycle arrest and apoptosis. The compound also interferes with the repair mechanisms of cancer cells, making them more susceptible to its cytotoxic effects .

Oxaliplatin wird oft mit anderen Platin-basierten Chemotherapeutika wie Cisplatin und Carboplatin verglichen. Während alle drei Verbindungen einen ähnlichen Wirkmechanismus teilen, hat this compound einzigartige Eigenschaften, die es von den anderen unterscheiden.

Ähnliche Verbindungen:

Cisplatin: Bekannt für seine Wirksamkeit bei der Behandlung von Hoden-, Eierstock- und Blasenkrebs. .

Carboplatin: Wird bei der Behandlung von Eierstock- und Lungenkrebs eingesetzt. .

Einzigartigkeit von this compound: this compound ist einzigartig in seiner Fähigkeit, stabilere DNA-Addukte zu bilden, was zu einer höheren Zytotoxizität in Krebszellen führt. Es hat auch ein anderes Nebenwirkungsprofil, mit einer geringeren Häufigkeit von Nephrotoxizität und Ototoxizität, aber einer höheren Häufigkeit von peripherer Neuropathie .

Zusammenfassend lässt sich sagen, dass this compound ein wichtiges Chemotherapeutikum ist, das in der wissenschaftlichen Forschung und in der klinischen Praxis eine breite Palette von Anwendungen findet. Seine einzigartigen Eigenschaften und sein Wirkmechanismus machen es zu einem wertvollen Werkzeug im Kampf gegen Krebs.

Oxaliplatin is a platinum-based chemotherapeutic agent primarily used in the treatment of colorectal cancer. Its unique chemical structure and mechanism of action differentiate it from other platinum compounds like cisplatin and carboplatin. This article provides a comprehensive overview of the biological activity of this compound, including its mechanisms, efficacy in clinical studies, and potential side effects.

This compound is characterized by the presence of a diaminocyclohexane (DACH) moiety, which enhances its antitumor activity compared to traditional platinum drugs. The mechanism of action involves the formation of DNA cross-links, which inhibit DNA replication and transcription, leading to cell death. Specifically, this compound forms intrastrand and interstrand cross-links primarily at the N7 position of guanine bases in DNA. This action complicates DNA repair mechanisms, making cancer cells more susceptible to its effects .

Key Mechanisms:

• DNA Cross-Linking: Formation of Pt-DNA adducts that prevent DNA replication.
• Immunogenic Cell Death: this compound can induce immunogenic signals in colon cancer cells, promoting an immune response against tumors .
• Cell Cycle Effects: The cytotoxicity is cell-cycle nonspecific, affecting various phases of the cell cycle .

Efficacy in Clinical Studies

Numerous clinical trials have evaluated the efficacy of this compound, particularly in combination with other agents such as fluorouracil (5-FU) and leucovorin (LV). The following table summarizes key findings from significant studies:

Case Studies

• Phase II Trial on Metastatic Colorectal Cancer :
  • Objective: Assess safety and efficacy.
  • Results: Nine patients showed partial responses; median duration was over 216 days. Main toxicity observed was peripheral sensory neuropathy .
• MOSAIC Trial :
  • Objective: Compare this compound with standard therapy for colon cancer.
  • Results: Patients receiving this compound had significantly improved survival rates compared to those receiving only fluorouracil .

Pharmacokinetics

The pharmacokinetics of this compound involve rapid distribution and non-enzymatic conversion into active metabolites post-administration. After intravenous infusion, the drug is primarily bound to plasma proteins, with a volume of distribution indicating extensive tissue uptake . The elimination half-life is approximately 30 hours, with renal excretion being a significant route for its metabolites.

Safety Profile and Side Effects

While this compound is effective against various cancers, it is associated with several side effects:

• Peripheral Neuropathy: A common dose-limiting toxicity that can be acute or cumulative.
• Hematologic Toxicities: Mild occurrences of neutropenia and thrombocytopenia.
• Gastrointestinal Issues: Nausea and vomiting are also reported but are generally manageable .

Basic Research Questions

Q. What are the pharmacodynamic distinctions between oxaliplatin and cisplatin, and how do these differences influence experimental design?

this compound differs from cisplatin in its DNA adduct formation and resistance mechanisms. Unlike cisplatin, this compound forms bulky platinum-DNA adducts that evade mismatch repair (MMR) detection, contributing to activity in MMR-deficient tumors . Experimental comparisons should include cytotoxicity assays across cell lines with varying MMR status (e.g., HCT116 MMR-proficient vs. MMR-deficient models) and use COMPARE analysis to evaluate differential gene expression profiles .

Q. How should researchers optimize combination therapies involving this compound in preclinical models?

Synergy studies require factorial experimental designs to test this compound with agents like 5-fluorouracil (5-FU) or bevacizumab. For example, in the NSABP C-07 trial, this compound combined with fluorouracil/leucovorin improved 3-year disease-free survival (78.2% vs. 72.9%; HR: 0.77, P=0.002) . Preclinical models should replicate clinical dosing schedules (e.g., FOLFOX regimens) and include endpoints like tumor growth delay and apoptosis markers (e.g., caspase-3 activation) .

Q. What experimental models best recapitulate this compound-induced neuropathy for mechanistic studies?

Rodent models using cumulative this compound doses (4–6 mg/kg/week) mimic chronic neuropathy. Assess mechanical allodynia via von Frey filaments and correlate with histopathological changes in dorsal root ganglia. In vitro models using sensory neurons can evaluate mitochondrial dysfunction and oxidative stress via Seahorse assays .

Advanced Research Questions

Q. How do molecular subtypes of colorectal cancer (CRC) predict this compound benefit?

CRC subtypes (e.g., CMS4/stem-like) show differential responses. In the NSABP C-07 trial, enterocyte-subtype stage III patients had significant this compound benefit (HR: 0.22, P=0.001 in discovery cohort), while stem-like subtypes showed no benefit (HR: 0.99, P=0.96) . Researchers should integrate transcriptomic profiling (e.g., RNA-seq) with clinical outcomes and validate findings using locked algorithms in independent cohorts .

Q. What biomarkers predict this compound resistance, and how can they be functionally validated?

BRAF mutations (e.g., V600E) are prognostic for poor survival (HR: 2.31 for post-recurrence survival, P<0.0001) but not predictive of this compound resistance . Validate candidates via CRISPR/Cas9 knock-in models and assess platinum-DNA adduct repair efficiency using comet assays. Correlate with ATP7A/B transporter expression in patient-derived organoids .

Q. How does this compound reintroduction impact survival in metastatic CRC, and what statistical methods adjust for confounding factors?

In the OPTIMOX1 trial, this compound reintroduction improved OS (HR: 0.56, P=0.009). Use Cox proportional hazards models with time-dependent covariates (e.g., progression events, second-line therapies) and shared frailty models to account for center-specific reintroduction rates .

Q. Methodological Guidance

Q. What statistical approaches are critical for analyzing this compound clinical trial data with heterogeneous subtypes?

• Stratified log-rank tests : Compare survival between treatment arms within molecular subgroups .
• Multivariate Cox models : Adjust for baseline risk factors (e.g., WBC, alkaline phosphatase) .
• Interaction tests : Evaluate treatment-by-subtype effects (e.g., enterocyte vs. stem-like) .

Q. How can network pharmacology models elucidate this compound’s off-target effects?

Integrate transcriptomic data (e.g., microarray profiling of pancreatic cancer cells) with protein interaction networks. Use systems biology tools like Cytoscape to identify hubs (e.g., autophagy-related proteins LC3B/Beclin-1) and validate via siRNA knockdown and functional assays (e.g., autophagosome quantification) .

Q. Contradictions and Validation

• vs. 11 : While molecular subtyping predicts this compound benefit in specific cohorts (e.g., enterocyte), BRAF mutations are prognostic but not predictive. Researchers must validate subtype-specific findings in independent trials and control for confounding variables like microsatellite instability .
• : this compound reintroduction improves survival, but trial designs should predefine reintroduction criteria to avoid selection bias.