The impact of folate status on the efficacy of colorectal cancer treatment

Our plain-English summary of The impact of folate status on the efficacy of colorectal cancer treatment, by L. Porcelli, Y.G. Assaraf, A. Azzariti, et al (Current Drug Metabolism, 2011).

The study

• Authors: L. Porcelli, Y.G. Assaraf, A. Azzariti, A. Paradiso, G. Jansen, G.J. Peters
• Journal: Current Drug Metabolism
• Published: 2011;12(10):975-84
• Type of article: Review
• Cited by: 13 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Over the past three decades, numerous reports have addressed several aspects of drug resistance phenomena. However, little is known regarding the impact that dietary components and nutritional supplements have on the mechanisms of resistance that malignant cells develop to chemotherapeutic agents. The increased fortification of cereals, grains and bread with folic acid (FA) has resulted in a marked rise in folate levels in blood and tissues. Vitamin fortification that includes FA is rather commonly used by cancer patients, but FA is also used to protect against pemetrexed induced side effects in the treatment of non-small cell lung cancer and mesothelioma or that of the antifolate methotrexate in rheumatoid arthritis. Moreover, the reduced folate leucovorin (LV, 5-formyltetrahydrofolate) is also used along with 5-fluorouracil in the treatment of colorectal cancer. Likewise, LV is used to reduce toxicity of methotrexate in the treatment of leukemia. FA can also increase efficacy of unrelated regimens, containing cisplatin. Hence there is growing evidence that dietary supplements as folic acid, can mimic, intensify, or attenuate the effects of unrelated chemotherapeutic agents. The aim of this review is to highlight some new insights in the cellular and molecular mechanisms affected by folate status, leading to chemotherapy resistance, especially towards antifolates in colorectal cancer treatment. This encompasses the effect of folate status on drug export, as well as on the increased expression of mutated target enzymes involved in folate metabolism and on the augmentation of cellular folate pools that impair polyglutamylation of antifolates, ultimately affecting treatment efficacy.

In plain English

This article was a review and was not about asbestos. The authors reviewed laboratory and clinical research on how folate status may affect colorectal cancer chemotherapy, especially 5-fluorouracil (5-FU) and antifolate drugs. Folate covered synthetic folic acid from fortified food or supplements, natural food and cellular folates, and the drug leucovorin. The review described evidence that two MTHFR gene variants cannot be considered reliable predictors of response to 5-FU-based chemotherapy. It also described preclinical studies in which cells adapted to low folate became more sensitive to antifolates. The authors proposed a model in which folate levels raise or lower drug-pumping proteins (BCRP and MRPs) depending on their location in the cell. In their own group's patient tumor data, tissue reduced folate levels remained raised 48 hours after 5-FU with high- or low-dose dl-leucovorin, compared with controls and 5-FU alone. A regimen using l-leucovorin did not change these folate levels. Inhibition of the 5-FU target enzyme was most pronounced with the high-folate treatment. The authors concluded that whether higher folic acid intake is beneficial or harmful is still debated.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: narrative review of preclinical and clinical studies
• Who was studied: No original study population. The authors reviewed published cell-line, animal and clinical studies. They also included earlier data from their own group on colon tumors (primary tumors and liver metastases) from 4 or 9 patients per treatment group, in the folate-pool figure.
• Exposure: Folate status covered three kinds of folate: synthetic folic acid from fortification or supplements, folates that occur naturally in food and inside cells, and leucovorin. The review looked at how folate status affects chemotherapy drugs used in colorectal cancer: 5-FU and antifolates such as methotrexate, raltitrexed and pemetrexed. No asbestos exposure was studied.
• Main results:
  • The review described evidence that the MTHFR C677T and A1298C gene variants cannot be considered reliable predictors of response to 5-FU-based chemotherapy in colorectal cancer patients.
  • Preclinical studies reviewed found that cancer cells adapted to low folate levels were more sensitive to antifolates.
  • Proposed model (part 1): when the drug-pump proteins BCRP and MRPs sit at the cell surface, folate supplementation increases their expression and/or activity.
  • Proposed model (part 2): when BCRP and MRPs sit inside the cell, the effect reverses. Folate supplementation decreases their expression and folate deprivation increases it.
  • A meta-analysis cited in the review (not this article's own data) reported tumor response rates of 21% with 5-FU plus folinic acid versus 11% with 5-FU alone, in patients with metastatic colorectal cancer.
  • In the authors' own patient tumor data, tissue levels of reduced folates remained raised about 48 hours after 5-FU with high-dose (500 mg/m2) or low-dose (25 mg/m2) dl-leucovorin. The comparison was with untreated controls and with patients given 5-FU alone.
  • In the same data, the regimen using l-leucovorin did not change reduced folate pools, although its effect on inhibition of thymidylate synthase was pronounced.
  • In the same data, the increase in reduced folates went with stronger inhibition of thymidylate synthase (the target of 5-FU), most pronounced with the high-folate treatment.
• The authors' conclusion: The authors concluded that higher folic acid intake may influence several biological processes. Whether the effects are always beneficial or harmful is still a matter of debate.
• Limitations the authors state:
  • The authors stated that the best dose of leucovorin to combine with 5-FU is still debated.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Colon cancer.

Medical terms in this study, explained in our Lexicon: Colorectal Cancer, Pemetrexed (Alimta), Non-Small Cell Lung Cancer, Mesothelioma, Antifolate, Fluorouracil (5-FU), Cisplatin, Chemotherapy.

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