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. 2015:2015:820543.
doi: 10.1155/2015/820543. Epub 2015 Apr 2.

Systemic chemotherapy is modulated by platelet-activating factor-receptor agonists

Ravi P Sahu  1 , Matheus Ferracini  2 , Jeffrey B Travers  3
Affiliations

Systemic chemotherapy is modulated by platelet-activating factor-receptor agonists

Ravi P Sahu et al. Mediators Inflamm. 2015.

Abstract

Chemotherapy is used to treat numerous cancers including melanoma. However, its effectiveness in clinical settings is often hampered by various mechanisms. Previous studies have demonstrated that prooxidative stressor-mediated generation of oxidized lipids with platelet-activating factor-receptor (PAF-R) agonistic activity induces systemic immunosuppression that augments the growth of experimental melanoma tumors. We have recently shown that treatment of murine B16F10 melanoma cells in vitro or tumors implanted into syngeneic mice and treated intratumorally with various chemotherapeutic agents generated PAF-R agonists in a process blocked by antioxidants. Notably, these intratumoral chemotherapy-generated PAF-R agonists augmented the growth of secondary (untreated) tumors in a PAF-R dependent manner. As both localized and systemic chemotherapies are used based on tumor localization/stage and metastases, the current studies were sought to determine effects of PAF-R agonists on systemic chemotherapy against experimental melanoma. Here, we show that systemic chemotherapy with etoposide (ETOP) attenuates the growth of melanoma tumors when given subsequent to the tumor cell implantation. Importantly, this ETOP-mediated suppression of melanoma tumor growth was blocked by exogenous administration of a PAF-R agonist, CPAF. These findings indicate that PAF-R agonists not only negatively affect the ability of localized chemotherapy but also compromise the efficacy of systemic chemotherapy against murine melanoma.

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Figures

Figure 1
Figure 1
Modulation of B16F10 tumor growth by systemic chemotherapy with etoposide (ETOP) and the effect of PAF-R agonist (CPAF). (a) Murine B16F10 melanoma tumor cells (0.5 × 106) were implanted into the shaved dorsal hind flanks of syngeneic C57BL/6-WT mice (5–7 mice/group) subcutaneously (day 0). Mice were treated with or without ETOP (36 mg/kg) intraperitoneally either at day 0, day 3, or day 6 repeated at every 3 days until the end of the experiment. Control mice received the vehicle (0.5% DMSO in 100 μL PBS) by the same route. Tumor growth was monitored and measured with digital caliper and tumor volume (major circumference × minor circumference2/2) was expressed as mean ± SEM per group. Statistical differences (∗∗ P > 0.01) were noted between vehicle and ETOP treatment (day 0) at day 15. (b) Following subcutaneous B16F10 tumor cell implantation, C57BL/6-WT mice were treated with or without ETOP (36 mg/kg) intraperitoneally at day 0 repeated every 3 days until the end of the experiment. CPAF treatment (250 ng/mouse) was given intraperitoneally at days 0, 6, and 12. Control mice received the vehicle (0.5% DMSO in 100 μL PBS) by the same route. Tumor growth was measured and tumor volume (major circumference × minor circumference2/2) was expressed as mean ± SEM per group and compared between the groups. Statistical differences were noted between (1) ∗∗ P < 0.01, vehicle and ETOP groups; (2) ∗ P < 0.05, vehicle and CPAF groups; and (3) ∗∗∗ P < 0.001, ETOP and CPAF and ETOP and ETOP + CPAF groups at day 15.
Figure 2
Figure 2
Effect of CPAF on EL4 tumor growth and comparison of basal B16F10 and EL4 tumor growth. (a) Murine syngeneic EL4 lymphoma tumor cells (0.5 × 106) were implanted subcutaneously into the shaved dorsal hind flanks of C57BL/6 WT mice (4-5 mice/group). CPAF treatment (250 ng/mouse) was given intraperitoneally at days 0, 6, and 12. Tumor growth was measured and tumor volumes (major circumference × minor circumference2/2) were compared between the groups. (b) The basal growth rates between B16F10 and EL4 tumors were compared by assessing tumor volumes (major circumference × minor circumference2/2). Statistical differences were noted between EL4 and B16F10 tumors at day 6 (∗∗∗ P < 0.001), day 9 (∗∗∗ P < 0.001), day 12 (∗∗∗ P < 0.001), and day 15 (∗∗ P < 0.01).
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