Page 47 - Read Online

Page 726 Bijnsdorp et al. Cancer Drug Resist 2021;4:719-27 https://dx.doi.org/10.20517/cdr.2021.21

combination with TPI would prevent such an effect. Therefore, it is of interest to explore combinations of
TAS-102 (which contains TPI) with rapamycin, which should include mechanistic studies evaluating, e.g.,
the phosphorylation status of Akt, mTOR, and p70/S6k.

In conclusion, resistance to rapamycin may be related to the activation of autophagy by TdR. To optimize
the use of mTOR inhibitors, it seems important to study the levels of TdR combined with intratumoral TP
expression.

DECLARATIONS
Authors’ contributions
Concept: Bijnsdorp IV, Peters GJ
Data collection: Bijnsdorp IV
Writing: Bijnsdorp IV, Peters GJ

Availability of data and materials
Not applicable.

Financial support and sponsorship
This study was supported by an educational grant from Taiho Pharmaceuticals, Tokushima, Japan.

Ethical approval and consent to participate
Not applicable.

Conflicts of interest
Both authors declared that there are no conflicts of interest.

Consent for publication
Not applicable.

Copyright
© The Author(s) 2021.

REFERENCES
1. Bruin M, Temmink OH, Hoekman K, Pinedo HM, Peters GJ. Role of platelet derived endothelial cell growth factor/thymidine
phosphorylase in health and disease. Cancer Therapy 2006;4:99-124.
2. Bronckaers A, Gago F, Balzarini J, Liekens S. The dual role of thymidine phosphorylase in cancer development and chemotherapy.
Med Res Rev 2009;29:903-53. DOI PubMed PMC
3. Ackland SP, Peters GJ. Thymidine phosphorylase: its role in sensitivity and resistance to anticancer drugs. Drug Resist Updat
1999;2:205-14. DOI PubMed
4. Brown NS, Bicknell R. Thymidine phosphorylase, 2-deoxy-D-ribose and angiogenesis. Biochem J 1998;334:1-8. DOI PubMed PMC
5. Liekens S, Bronckaers A, Pérez-Pérez MJ, Balzarini J. Targeting platelet-derived endothelial cell growth factor/thymidine
phosphorylase for cancer therapy. Biochem Pharmacol 2007;74:1555-67. DOI PubMed
6. Matsushita S, Nitanda T, Furukawa T, et al. The effect of a thymidine phosphorylase inhibitor on angiogenesis and apoptosis in
tumors. Cancer Res 1999;59:1911-6. PubMed
7. Mayer RJ, Van Cutsem E, Falcone A, et al. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med
2015;372:1909-19. DOI PubMed
8. Peters GJ. Therapeutic potential of TAS-102 in the treatment of gastrointestinal malignancies. Ther Adv Med Oncol 2015:7;340-56.
DOI PubMed PMC
9. Peters GJ, Bijnsdorp IV. TAS-102: more than an antimetabolite. Lancet Oncol 2012;13:e518-9. DOI PubMed
10. Bijnsdorp IV, Azijli K, Jansen EE, et al. Accumulation of thymidine-derived sugars in thymidine phosphorylase overexpressing cells.
Biochem Pharmacol 2010;80:786-92. DOI PubMed
11. Hotchkiss KA, Ashton AW, Schwartz EL. Thymidine phosphorylase and 2-deoxyribose stimulate human endothelial cell migration by
specific activation of the integrins alpha 5 beta 1 and alpha V beta 3. J Biol Chem 2003;278:19272-9. DOI PubMed