Dopamine is a safe antiangiogenic drug which can also prevent 5-fluorouracil induced neutropenia

Abstract

The role of vascular endothelial growth factor A (VEGFA) in tumor angiogenesis is well established and accordingly, molecules targeting VEGFA or its receptors are being presently used in the clinics for treatment of several types of cancer. However, these antiangiogenic agents are expensive and have serious side effects. Thus identification of newer drugs with manageable systemic side effects or toxicities is of immense clinical importance. Since we have reported earlier that dopamine (DA) inhibits VEGFA induced angiogenesis in experimental tumor models, we therefore sought to investigate whether DA treatment results in similar toxicities like other antiangiogenic agents. Our results indicated that unlike sunitinib, another commonly used antiangiogenic agent in the clinics which targets VEGF receptors, DA [50 mg/kg/days × 7days intraperitoneally (i.p.)] not only could inhibit tumor angiogenesis and growth of HT29 human colon cancer and LLC (Lewis lung carcinoma) in mice, it also did not cause hypertension, hematological, renal and hepatic toxicities in normal, HT29 and LLC tumor bearing animals. Furthermore and interestingly, in contrast to the currently used antiangiogenic agents, DA also prevented 5-fluorouracil (5FU) induced neutropenia in HT29 colon cancer bearing mice. This action of DA was through inhibition of 5FU mediated suppression of colony forming unit-granulocyte macrophage colony forming units in the bone marrow. Thus our results indicate that DA may be safely used as an antiangiogenic drug for the treatment of malignant tumors.

Keywords: 5-FU; antiangiogenic drugs; colon cancer; dopamine; lung cancer; toxicity.

Figure 1

Dopamine (DA) treatment significantly reduced the growth of (a) orthotopic HT29 colon cancer and (b) subcutaneous lewis lung carcinoma (LLC) tumors as compared to untreated tumors. Tumor angiogenesis was also significantly reduced in dopamine treated (c) HT29 and (d) LLC tumors compared to respective untreated controls. In contrast to sunitinib, dopamine treatment had no significant effect on the diastolic, systolic and mean blood pressures of normal (e) athymic nude and (f) C57/BL6 mice. Results are mean ± SE of three separate experiments; n=13 per group;*P < 0.05 when compared to respective controls.

Figure 2

In contrast to sunitinib, dopamine (DA) treatment had no significant toxic effect on liver and renal functions compared to untreated controls as was determined by (a) alanine aminotransferase (ALT) (b) aspartate aminotransferase (AST) (c) total bilirubin (TBILI) (d) blood urea nitrogen (BUN) and (e) Creatinine (Creat) levels in serum of untreated and treated (DA and sunitinib) normal, HT29 and LLC tumor bearing mice. Results are mean ± SE of three separate experiments; n=13 per group;*P < 0.05 when compared to respective controls.

Figure 3

In comparison to sunitinib, dopamine (DA) treatment showed no hematological toxicity as determined by measuring the (a) platelet (PLT) (b) neutrophil (NE) and (c) hemoglobin (Hb) levels in blood of DA and sunitinib treated normal, HT29 and LLC tumor bearing mice and comparing to untreated controls. (d).Combination treatment of DA and 5FU of HT29 tumor bearing mice prevented 5 FU induced significant reduction of NE counts (*P < 0.05 when compared to control; + P < 0.05 when compared to 5FU treated group). (e) The number of CFU-GM colonies in culture significantly increased when bone marrow cells were collected from mice receiving combination treatment of DA and 5FU compared to 5 FU alone. *P < 0.05 when compared to normal; + P < 0.05 when compared to 5FU treated group. Results are mean ± SE of three separate experiments; n=13 per group.