5-methyltetrahydrofolate and Lung-Neoplasms

Topics: Adenocarcinoma; Adult; Aged; Clinical Trials as Topic; Colonic Neoplasms; Drug Therapy, Combination; Female; Fluorouracil; Humans; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Pelvic Neoplasms; Rectal Neoplasms; Tetrahydrofolates

Tobacco smoking is a major known risk factor for lung cancer. While micronutrients, especially those involved in maintaining DNA integrity and regulating gene expression, may be protective, research on this association is limited. This report aimed to investigate associations of total folate, 5-methyltetrahydrofolate (5-mTHF) and vitamin B12 with incident risk of lung cancer, and whether the associations vary by smoking status. A nested case-control study with 490 incident lung cancer cases and 490 controls matched by age (±1 year), sex, residence, and center, drawn from a community-based prospective study in China, was conducted from 2016 to 2019. 5-mTHF accounted for the majority of total folate. Only 4.4% had detectable unmetabolized folic acid. Lung cancer cases had lower levels of 5-mTHF compared to controls. There was an inverse, nonlinear association between 5-mTHF and lung cancer, which persisted after adjustment for covariables (P for trend = .001). Compared to the lowest 5-mTHF quartile, those in higher quartiles had lower risks of lung cancer: second quartile OR = 0.65; 95% CI: 0.45-0.93; third quartile OR = 0.50; 95% CI: 0.34-0.74; fourth quartile OR = 0.56; 95% CI: 0.38-0.83. This inverse association was more pronounced among ever smokers; consistently, the highest risk of lung cancer (OR = 3.21, 95% CI: 1.97-5.24) was observed among ever smokers with low 5-mTHF levels compared to participants who never smoked and had higher 5-mTHF levels. Vitamin B12 was not associated with lung cancer risk. In this sample of Chinese adults without confounding by unmetabolized folic acid, higher levels of 5-mTHF were associated with lower risk of incident lung cancer.

Topics: Adult; Case-Control Studies; Folic Acid; Humans; Lung Neoplasms; Prospective Studies; Risk Factors; Vitamin B 12; Vitamins

Pemetrexed is a novel antifolate recently approved for the treatment of pleural mesothelioma and non-small cell lung cancer. In clinical regimens, pemetrexed is administered in conjunction with folic acid to minimize toxicity. However, excessive folate supplementation may also diminish the activity of this agent. The current study demonstrates, in several human solid tumor cell lines, that when extracellular 5-formyltetrahydrofolate levels are increased in vitro, within the range of normal human blood levels, there is a substantial decrease in pemetrexed activity upon continuous exposure to the drug. This was accompanied by a comparable lower level of trimetrexate activity consistent with an expansion of tumor cell folate pools. Likewise, when cells were exposed to pemetrexed with a schedule that simulates in vivo pharmacokinetics, there was markedly less cell killing with higher extracellular folate levels. Data are provided to indicate that 5-formyltetrahydrofolate is an acceptable surrogate for 5-methyltetrahydrofolate, the major blood folate, for this type of in vitro study. These observations and other reports suggest that, in view of the rise in serum folate and fall in serum homocysteine that has accompanied folic acid supplementation of food in the U.S., the addition of folic acid to regimens with pemetrexed should be limited to the lowest recommended level that provides optimal protection from pemetrexed toxicity.

Topics: Antimetabolites, Antineoplastic; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Colorectal Neoplasms; Folic Acid; Folic Acid Antagonists; Glutamates; Guanine; Humans; In Vitro Techniques; Lung Neoplasms; Mesothelioma; Pemetrexed; Tetrahydrofolates

Thirty-eight patients with advanced colorectal adenocarcinoma were treated with the following regimen: N5-10-methyltetrahydrofolate (MTHF) (200 mg/m2/day) and 5-fluorouracil (5-FU) (375 mg/m2/day) given concomitantly, consecutively for 5 days, every 4 weeks, in order to evaluate the potential advantage derived from the biochemical enhancement of cytotoxic activity of 5-FU by high-dose reduced folates. Of 33 evaluable patients (six of whom had received prior 5-FU chemotherapy) three untreated patients achieved a partial response (9.1%) lasting 84, 281 and 401 days; 24 patients (72.7%) had stable disease lasting a median of 150 days (range 60-304 days). The overall toxicity was acceptable: two patients had severe cardiac symptoms. Pharmacokinetics and biochemical studies seem necessary to determine the optimal dosage and timing of 5-FU and folates.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Drug Evaluation; Female; Fluorouracil; Humans; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Rectal Neoplasms; Tetrahydrofolates