Impaired microvascular reactivity in patients treated with 5-fluorouracil chemotherapy regimens: Potential role of endothelial dysfunction

Figures

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  Fig. 1. Impaired cutaneous microvascular reactivity following local heating in cancer patients treated with 5-FU. A) A representative tracing of the rise in CVC from baseline during a 35-minute local heating protocol for a 5-FU treated patient (5-FU, Male 64 years old) and matched control (CON, Male, 63 years old). B) 5-FU patients (n = 17, 7 women) presented with a significantly lower %ΔCVC than control subjects (n = 20, 9 women) (CON: 566 ± 305 %; 5-FU: 282 ± 172 %; P = 0.001, ES = 0.93) following 35-minutes of local heating suggesting the presence of impairment along the eNOS-NO vasodilator pathway following 5-FU chemotherapy. Data were compared using the Welch’s t-test and presented as mean ± SD.

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  Fig. 2. L-NAME fails to reduce the local heating response in 5-FU-treated cancer patients. A) L-NAME iontophoresis significantly reduced the %ΔCVC response to local heating in control participants (n = 7, 3 women) (SH: 564 ± 371 %; L + SH: 175 ± 122 %; P = 0.03, ES = 1.05) but not in patients undergoing cancer treatment with 5-FU (n = 7, 3 women) (SH: 327 ± 118 %; L + SH: 333 ± 227 %; P = 0.95, ES = 0.03) suggesting a lesser contribution of NO to the heated plateau following treatment with 5-FU chemotherapy. B) The absolute difference in the percent change between the SH and L treated sites was significantly greater in control participants compared to 5-FU treated cancer patients (CON: 389 ± 388 %; 5-FU: −6 ± 247 %; P = 0.04, ES = 1.21). SH = standard heating; L + SH = L-NAME + standard heating. Data were compared using Welch’s t-test (A, control cohort) and independent-samples t-test (A, 5-FU cohort; B) and presented as mean ± SD.

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  Fig. 3. Cutaneous microvascular reactivity in response to ACh iontophoresis is maintained in 5-FU-treated cancer patients. A) ACh iontophoresis resulted in a significant rise in %ΔCVC with successive ACh impulses (P = < 0.001); however, this rise was not different between patients treated with 5-FU (n = 17, 4 women) and control subjects (n = 15, 7 women) (P = 0.44). B) This finding was corroborated by the similarity in the peak response to ACh between groups (CON: 920 ± 416 %; 5-FU: 835 ± 448 %; P = 0.58), suggesting some endothelium-dependent vasodilatory pathways may remain intact following 5-FU-based chemotherapy. Data were compared using two-way repeated measures ANOVA (A) and independent- samples t-test (B). All data are presented as mean ± SD.

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  Fig. 4. eNOS gene expression is reduced in 5-FU treated HCAEC. There was a significant main effect for differences in eNOS gene expression between the groups following the 24-hr. incubation period (P = 0.002, ES = 0.72). CON cells (1.114 ± 0.06 a.u) had significantly higher levels of eNOS gene expression compared to cells treated with both 0.7 mM (0.711 ± 0.12 a.u; P = 0.008, ES = 0.52) and 7.0 mM (0.578 ± 0.13 a.u; P = 0.002, ES = 0.69) of 5-FU, while no differences were detected between the two 5-FU concentrations (P = 0.34). n = 3 cultures per group. All samples were run in duplicate. Data were analyzed using One-way ANOVA and are presented as mean ± SD. a.u. = arbitrary units. eNOS = endothelial nitric oxide synthase.