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Exposure-dependent incorporation of trifluridine into DNA of tumors and white blood cells in tumor-bearing mouse

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Abstract

Purpose

Trifluridine (TFT) is an antitumor component of a novel nucleoside antitumor agent, TAS-102, which consists of TFT and tipiracil hydrochloride (thymidine phosphorylase inhibitor). Incorporation of TFT into DNA is a probable mechanism of antitumor activity and hematological toxicity. The objective of this study was to examine the TFT incorporation into tumor- and white blood cell-DNA, and to elucidate the mechanism of TFT-related effect and toxicity. TFT effect on the colony formation of mouse bone marrow cells was also investigated.

Methods

Pharmacokinetics of TFT was determined in nude mice after single oral administration of TAS-102, while the antitumor activity and body weight change were evaluated in the tumor-bearing nude mice after multiple oral administrations for 2 weeks. TFT concentrations in the blood- and tumor-DNA were determined by LC/MS/MS. The colony formation was evaluated by CFU-GM assay.

Results

TFT systemic exposure in plasma increased dose-dependently. The tumor growth rate and body weight gain decreased dose-dependently, but TFT concentrations in the DNA of tumor tissues and white blood cells increased dose-dependently. TFT inhibited colony formation of bone marrow cells in a concentration-dependent manner.

Conclusions

A significant relationship between systemic exposure of TFT and pharmacological effects including the antitumor activity and body weight change was well explained by the TFT incorporation into DNA. TFT inhibited proliferations of mouse bone marrow cells and human colorectal carcinoma cells implanted to nude mice dose-dependently. The highest tolerable TFT exposure provides the highest antitumor activity, and the hematological toxicity may serve as a potential surrogate indicator of TAS-102 efficacy.

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Abbreviations

AZT:

Zidovudine

TFT:

Trifluridine

C max :

Maximum plasma concentration

AUC:

Area under plasma concentration–time curve

AUC0–t :

AUC from time 0 to the time (t) of the last quantifiable concentration

AUC0–12h :

AUC from time 0 to the last time point (12 h)

TPI:

Tipiracil hydrochloride

BW:

Body weight

LLOQ:

Lower limit of quantification

LC/MS/MS:

Liquid chromatography–tandem mass spectrometry

FTY:

Trifluorothymine

HPMC:

Hydroxypropyl methylcellulose

PK:

Pharmacokinetics

PD:

Pharmacodynamics

TV:

Tumor volume

RTV:

Relative tumor volume

TGI:

Tumor growth inhibition rate

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Acknowledgments

We thank Dr. Kiyoshi Morikawa for providing the KM20C cells. All authors are employees of Taiho Pharmaceutical Co., Ltd., the company that developed TAS-102.

Conflict of interest

Authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Pharmacokinetics Research Laboratories, Taiho Pharmaceutical Co., Ltd., 3 Okubo, Tsukuba, Ibaraki, 300-2611, Japan

    Fumiaki Yamashita, Ikumi Komoto, Keizo Kuwata, Mayuko Takeuchi, Kunihiro Yoshisue & Masato Chiba

  2. Toxicology Laboratory, Taiho Pharmaceutical Co., Ltd., 224-2 Ebisuno, Hiraishi, Kawauchi-cho, Tokushima, 771-0194, Japan

    Hiroaki Oka

  3. Optimal Medication Research Laboratory, Taiho Pharmaceutical Co., Ltd., 224-2 Ebisuno, Hiraishi, Kawauchi-cho, Tokushima, 771-0194, Japan

    Fumio Nakagawa

Authors
  1. Fumiaki Yamashita
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  2. Ikumi Komoto
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  3. Hiroaki Oka
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  4. Keizo Kuwata
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  5. Mayuko Takeuchi
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  6. Fumio Nakagawa
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  7. Kunihiro Yoshisue
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  8. Masato Chiba
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Corresponding author

Correspondence to Fumiaki Yamashita.

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Yamashita, F., Komoto, I., Oka, H. et al. Exposure-dependent incorporation of trifluridine into DNA of tumors and white blood cells in tumor-bearing mouse. Cancer Chemother Pharmacol 76, 325–333 (2015). https://doi.org/10.1007/s00280-015-2805-9

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  • DOI: https://doi.org/10.1007/s00280-015-2805-9

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