ma-1 and Brain-Neoplasms

Overexpressed human thymidine phosphorylase (hTP) has been associated with cancer aggressiveness and poor prognosis by triggering proangiogenic and antiapoptotic signaling. Designed as transition-state analogues by mimicking the oxacarbenium ion, novel pyrimidine-2,4-diones were synthesized and evaluated as inhibitors of hTP activity. The most potent compound (8g) inhibited hTP in the submicromolar range with a noncompetitive inhibition mode with both thymidine and inorganic phosphate substrates. Furthermore, compound 8g was devoid of apparent toxicity to a panel of mammalian cells, showed no genotoxicity signals, and had low probability of drug-drug interactions and moderate in vitro metabolic rates. Finally, treatment with 8g (50 mg/(kg day)) for 2 weeks (5 days/week) significantly reduced tumor growth using an in vivo glioblastoma model. To the best of our knowledge, this active compound is the most potent in vitro hTP inhibitor with a kinetic profile that cannot be reversed by the accumulation of any enzyme substrates.

Topics: Animals; Area Under Curve; Brain Neoplasms; Cell Line; Cell Line, Tumor; Drug Design; Enzyme Inhibitors; Glioblastoma; Half-Life; Humans; Thymidine Phosphorylase

A woman in her 70s was confirmed as presenting with multiple liver and lung metastases from transverse colon cancer. After undergoing resection of the primary lesion, partial response(PR)was achieved after undergoing the first regimen (sLV5FU2 and bevacizumab[Bmab]); therefore, partial hepatectomy was performed. Adjuvant chemotherapy was administered for 7 months, but liver metastasis recurrence, multiple lung metastases, and brain metastasis were confirmed. As the brain metastasis was a single lesion and was accompanied by symptoms, resection of the lesion was performed. Treatment with regorafenib was initiated, but Grade 3 severe erythema multiforme was detected, and the treatment had to be discontinued. Therefore, combined TFTD and Bmab therapy was initiated as the third regimen. Liver and lung metastases were maintained as stable disease(SD), and the treatment was continued for approximately 1 year together with stereotaxic radiation therapy for the newbrain metastatic lesion. The utility of combined TFTD and Bmab therapy has been reported in a phase II trial, and it has also been indicated that Bmab is effective for reducing brain edema. As this treatment was effective in this case, we will report on it together with a discussion of the literature.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Brain Neoplasms; Colonic Neoplasms; Female; Humans; Pyrrolidines; Thymine; Trifluridine