Abstract
The stock of therapeutic weapons available in metastatic colorectal cancer (mCRC) has been progressively grown over the years, with improving both survival and patients' clinical outcome: notwithstanding advances in the knowledge of mCRC biology, as well as advances in treatment, fluoropyrimidine antimetabolite drugs have been for 30 years the mainstay of chemotherapy protocols for this malignancy. 5-Fluorouracil (5FU) seems to act differently depending on administration method: elastomer-mediated continuous infusion better inhibits Thymidylate Synthase (TS), an enzyme playing a pivotal role in DNA synthetic pathway. TS overexpression is an acknowledged poor prognosis predicting factor. The simultaneous combination of 5FU and folinate salt synergistically strengthens fluorouracil cytotoxic effect. In our experience, levofolinate and 5FU together in continuous infusion prolong progression free survival of patients suffering from mCRC, moreover decreasing death risk and showing a clear clinical benefit for patients, irrespective of RAS mutational status, primitive tumor side and metastases surgery.
Highlights
Notwithstanding advances in the knowledge of metastatic colorectal cancer biology, as well as advances in treatment, fluoropyrimidine antimetabolite drugs (5-fluorouracil – FUra, 5FU, 5-fluoro-2’deoxyuridine – 5FUdR, 5’-deoxy-5-fluoro-N-[(pentyloxy) carbonyl]-cytidine – capecitabine, an oral FUra prodrug) are currently the mainstay of chemotherapy protocols for this malignancy. 5FU seems to act differently depending on administration method: quick bolus mainly increases incorporation of 5FU in RNA [1], even yielding a more severe hematological and gastrointestinal toxicity than continuous infusion [2], whereas elastomer-mediated continuous infusion long inhibits Thymidylate Synthase (TS) [3, 4]
The stock of therapeutic weapons available in metastatic colorectal cancer has been progressively grown over the years, with improving both survival and patients' clinical outcome: notwithstanding advances in the knowledge of mCRC biology, as well as advances in treatment, fluoropyrimidine antimetabolite drugs have been for 30 years the mainstay of chemotherapy protocols for this malignancy. 5-Fluorouracil (5FU) seems to act differently depending on administration method: elastomer-mediated continuous infusion better inhibits Thymidylate Synthase (TS), an enzyme playing a pivotal role in DNA synthetic pathway
The number of patients treated with therapy based on calcium-levolinate and sodium-levolinate were 105 and 95, respectively: between the two groups, no statistically significant difference has been found, but median follow up duration – 28,8 for CaLF vs 18,8 months for NaLF, p value 0,0001 (Mann-Whitney U Test)
Summary
Notwithstanding advances in the knowledge of metastatic colorectal cancer (mCRC) biology, as well as advances in treatment, fluoropyrimidine antimetabolite drugs (5-fluorouracil – FUra, 5FU, 5-fluoro-2’deoxyuridine – 5FUdR, 5’-deoxy-5-fluoro-N-[(pentyloxy) carbonyl]-cytidine – capecitabine, an oral FUra prodrug) are currently the mainstay of chemotherapy protocols for this malignancy. 5FU seems to act differently depending on administration method: quick bolus mainly increases incorporation of 5FU in RNA [1], even yielding a more severe hematological and gastrointestinal toxicity than continuous infusion [2], whereas elastomer-mediated continuous infusion long inhibits Thymidylate Synthase (TS) [3, 4]. Preclinical evidence has pointed out that culture medium containing folinic acid increases 5FU-mediated cell growth inhibition and cytotoxicity (Figure 1). Folinic acid acts as a “stabilizer” of fluoropyrimidines and TS, with accumulating inactive complexes [7, 8].
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