Effect of the Tumor Vascular-Damaging Agent, ZD6126, on the Radioresponse of U87 Glioblastoma

Abstract

Purpose: The effect of ZD6126 on tumor oxygen tension and tumor growth delay in combination with ionizing radiation was examined in the human U87 glioblastoma tumor model. Resistance to ZD6126 treatment was investigated with the nitric oxide synthase inhibitor, l-NG-nitroarginine methyl ester (hydrochloride; l-NAME/active form, l-NNA). Methods: U87 human xenografts were grown in athymic nude mice. ZD6126 was given with or without l-NNA. Tumor oxygen tension was measured using the Oxford Oxylite (Oxford, England) fiberoptic probe system. Tumor volume was determined by direct measurement with calipers and calculated by the formula [(smallest diameter2 × widest diameter)/2]. Results: Multiple doses of ZD6126 treatment (three doses) had a significant effect on tumor growth delay, reducing the average daily tumor growth rate from 29% to 16%. When given 1 hour before radiation, ZD6126 caused an acute increase in hypoxia in U87 tumors, and reduced tumor growth delay compared with that of radiation alone. The combination of ZD6126 given after radiation, either as a single dose or in multiple doses, had greater or similar antitumor activity compared with radiation alone. Twenty-four hours after administration, a single dose of ZD6126 induced little (10 ± 8%) necrosis in U87 xenografts. l-NNA, when given in combination with ZD6126, significantly enhanced the effectiveness of ZD6126 in inducing tumor necrosis. Conclusions: Our observation that ZD6126-induced tumor hypoxia can decrease radiation response when ZD6126 is given prior to radiation indicates the importance of scheduling. Our findings suggest that the optimal therapeutic benefit of ZD6126 plus radiation in human glioblastoma may require multiple dosing in combination with a nitric oxide synthase inhibitor, to be scheduled following radiotherapy.

Diffuse optical spectroscopy assessment of rodent tumor model oxygen state after single-dose irradiation

“…Simultaneously, the tumor increases the access of oxygen to previously hypoxic cells, which again increases their sensitivity to radiation [10]. It should be mentioned that involvement of changes in oxygen consumption and blood flow to reoxygenation processes can be different [4].…”

“…increase in oxygen partial pressure after irradiation was described for conventional radiotherapy regimens at the same time [2]. By irradiation with standard conventional single doses (1.8-2 Gy), a minimal vessels' damage and a death of definite number of tumor cells appeared to be a main mechanism of reoxygenation due to decrease in oxygen consumption and increase in the perfusion [3,4]. For many years, conventional irradiation has been a 'gold standard' of radiation therapy.…”

Feedback loop between hypoxia and energy metabolic reprogramming aggravates the radioresistance of cancer cells

“…Traditionally, it was believed that anti-angiogenic agents would inhibit tumor angiogenesis, depriving the tumor of essential nutrients and oxygen. However, studies have shown that in tumor, excessive angiogenic factors can cause poor and disturbed vascular blood flow and leakage, leading to poor drug delivery and hypoxia [ 149 ]. In this pathological condition, angiogenic factors, acting as the “abnormalization factor”, promote a vascular “abnormalization switch” [ 150 ].…”

“…Elucidation of the molecular mechanisms of pathological angiogenesis and the homeostatic regulation of angiogenic factors may provide new targets for improving the radiosensitivity of cancer cells. Tumor growth and angiogenesis are an interdependent cycle that can be broken by antiangiogenic therapy, thereby reducing radioresistance [ 170 ]. However, irradiation and anti-angiogenic therapies can cause angiogenesis to switch from sprouting to intussusception.…”

Evaluating the effects of radiation and acoustically-stimulated microbubble therapy in an in vivo breast cancer model

“…Tumor blood vessels exhibit abnormal and rapid growth caused by aberrant cell signaling leading to weak, tortuous, and leaky vasculature. As such, tumor vasculature is an attractive target for cancer therapies [ 3 , 4 ]. Anti-vascular agents such as microtubule destabilizing drugs and flavonoids can disrupt the tumor vasculature [ 5 ].…”