FTD Anticancer Drug Dosing via Thymidine Phosphorylase Inhibitor

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Solution Overview

Problem

α,α,α-Trifluorothymidine (FTD) has a short half-life due to degradation by thymidine phosphorylase, leading to inadequate therapeutic effects and adverse toxicities in cancer treatment, especially when administered once daily, with limited survival benefits and significant side effects.

Innovation Solution

Administering FTD in combination with a thymidine phosphorylase inhibitor (TPI) at a molar ratio of 1:0.5 in 2 to 4 divided oral doses, allowing for increased blood concentration and reduced dosing to 20 to 80 mg/m2/day, which enhances antitumor activity and reduces side effects.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Ease of operation

If FTD is administered once daily, then the administration is simple and general usage is improved, but the therapeutic effect is insufficient and bone marrow suppression occurs

Engineering Contradiction:

Improveadministration simplicityVSAvoidtherapeutic effect

Core Design Contradiction:

Ease of operationVSReliability

Solution Approach 1:

The patent divides the daily FTD dosage into multiple administrations (2-4 times daily) to maintain effective blood concentrations throughout the day. This segmentation of the dosing schedule resolves the contradiction by preserving therapeutic effectiveness while maintaining administrative simplicity through standardized multiple dosing intervals.

Inventive Principle:

Principle #1Segmentation

2Reliability

If FTD is administered at high doses to achieve therapeutic effect, then antitumor activity increases, but bone marrow suppression and gastrointestinal toxicities worsen

Engineering Contradiction:

Improveantitumor activityVSAvoidbone marrow suppression

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent introduces TPI (thymidine phosphorylase inhibitor) as an intermediary substance that prevents FTD degradation. By adding TPI to the formulation, the patent maintains effective FTD blood concentrations at lower doses, thereby achieving antitumor activity while reducing bone marrow suppression and gastrointestinal toxicities associated with high-dose FTD monotherapy.

Inventive Principle:

Principle #24Intermediary (Mediator)

3Device complexity

If FTD is administered without TPI, then the formulation is simple, but FTD is rapidly degraded and half-life is extremely short (12 minutes)

Engineering Contradiction:

Improveformulation complexityVSAvoidFTD half-life

Core Design Contradiction:

Device complexityVSDuration of action of moving object

Solution Approach 1:

The patent adds TPI as an intermediary substance that inhibits thymidine phosphorylase, the enzyme responsible for FTD degradation. This formulation combination extends FTD half-life from 12 minutes to several hours by preventing enzymatic breakdown, thereby resolving the contradiction between formulation simplicity and drug stability.

Inventive Principle:

Principle #24Intermediary (Mediator)

4Reliability

If FTD is administered at 100 mg/m2/day to achieve therapeutic effect, then tumor regression is observed, but the dose is high and side effects increase

Engineering Contradiction:

Improvetherapeutic effectVSAvoidtotal daily dose

Core Design Contradiction:

ReliabilityVSQuantity of substance

Solution Approach 1:

By incorporating TPI as a protective intermediary, the patent enables achievement of therapeutic effects at reduced FTD doses (20-80 mg/m2/day). The TPI prevents FTD degradation, maintaining effective blood concentrations without requiring high total daily doses, thus resolving the contradiction between therapeutic effectiveness and dosage quantity.

Inventive Principle:

Principle #24Intermediary (Mediator)

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

This approach significantly increases antitumor activity and improves therapeutic outcomes while reducing the total daily dose, maintaining effective FTD levels in DNA and managing side effects, as demonstrated in clinical trials and animal models.

Implementation Method 1

FTD is degraded by a thymidine phosphorylase (TP) in a human body after intravenous administration... the applicant has discovered 5-chloro-6-(1-(2-iminopyrrolidinyl)methyl)uracil hydrochloride (see the structural formula below), a thymidine phosphorylase inhibitor (TPI) for preventing FTD degradation

Methodology Applied

Scientific EffectEnzyme inhibition: Enzyme

Implementation Method 2

FTD has no effect on RNA, and is phosphorylated by an intracellular thymidine kinase to form a monophosphorylated form, namely, trifluorothymidine monophosphate (F3TMP). The F3TMP binds to a thymidylate synthase (TS) to exhibit a DNA synthesis-inhibiting effect

Methodology Applied

Scientific EffectPhosphorylation:

Data Source

PatentUSRE46284E1Method of administrating an anticancer drug containing α, α, α-trifluorothymidine and thymidine phosphorylase inhibitor

Publication Date: 2017.01.24 TAIHO PHARMA CO LTD

AI summary

The present invention relates to a method for treating a cancer comprising orally administering a composition containing α,α,α-trifluorothymidine (FTD) and 5-chloro-6-(1-(2-iminopyrrolidinyl)methyl)uracil hydrochloride in a molar ratio of 1:0.5 at a dose of 20 to 80 mg/m2/day in terms of FTD in 2 to 4 divided portions per to patients in need of the treatment.