Radiosensitizing Pancreatic Cancer Xenografts by an Implantable Micro-Oxygen Generator.

Over the past decades, little progress has been made to improve the extremely low survival rates in pancreatic cancer patients. Extreme hypoxia observed in pancreatic tumors contributes to the aggressive and metastatic characteristics of this tumor and can reduce the effectiveness of conventional radiation therapy and chemotherapy. In an attempt to reduce hypoxia-induced obstacles to effective radiation treatment, we used a novel device, the implantable micro-oxygen generator (IMOG), for in situ tumor oxygenation. After subcutaneous implantation of human pancreatic xenograft tumors in athymic rats, the IMOG was wirelessly powered by ultrasonic waves, producing 30 µA of direct current (at 2.5 V), which was then utilized to electrolyze water and produce oxygen within the tumor. Significant oxygen production by the IMOG was observed and corroborated using the NeoFox oxygen sensor dynamically. To test the radiosensitization effect of the newly generated oxygen, the human pancreatic xenograft tumors were subcutaneously implanted in nude mice with either a functional or inactivated IMOG device. The tumors in the mice were then exposed to ultrasonic power for 10 min, followed by a single fraction of 5 Gy radiation, and tumor growth was monitored thereafter. The 5 Gy irradiated tumors containing the functional IMOG exhibited tumor growth inhibition equivalent to that of 7 Gy irradiated tumors that did not contain an IMOG. Our study confirmed that an activated IMOG is able to produce sufficient oxygen to radiosensitize pancreatic tumors, enhancing response to single-dose radiation therapy.

Monitoring the effects of anti-angiogenesis on the radiation sensitivity of pancreatic cancer xenografts using dynamic contrast-enhanced computed tomography.

PURPOSE: To image the intratumor vascular physiological status of pancreatic tumors xenografts and their response to anti-angiogenic therapy using dynamic contrast-enhanced computed tomography (DCE-CT), and to identify parameters of vascular physiology associated with tumor x-ray sensitivity after anti-angiogenic therapy. METHODS AND MATERIALS: Nude mice bearing human BxPC-3 pancreatic tumor xenografts were treated with 5 Gy of radiation therapy (RT), either a low dose (40 mg/kg) or a high dose (150 mg/kg) of DC101, the anti-VEGF receptor-2 anti-angiogenesis antibody, or with combination of low or high dose DC101 and 5 Gy RT (DC101-plus-RT). DCE-CT scans were longitudinally acquired over a 3-week period post-DC101 treatment. Parametric maps of tumor perfusion and fractional plasma volume (Fp) were calculated and their averaged values and histogram distributions evaluated and compared to controls, from which a more homogeneous physiological window was observed 1-week post-DC101. Mice receiving a combination of DC101-plus-RT(5 Gy) were imaged baseline before receiving DC101 and 1 week after DC101 (before RT). Changes in perfusion and Fp were compared with alternation in tumor growth delay for RT and DC101-plus-RT (5 Gy)-treated tumors. RESULTS: Pretreatment with low or high doses of DC101 before RT significantly delayed tumor growth by an average 7.9 days compared to RT alone (P ≤ .01). The increase in tumor growth delay for the DC101-plus-RT-treated tumors was strongly associated with changes in tumor perfusion (ΔP>-15%) compared to RT treated tumors alone (P=.01). In addition, further analysis revealed a trend linking the tumor's increased growth delay to its tumor volume-to-DC101 dose ratio. CONCLUSIONS: DCE-CT is capable of monitoring changes in intratumor physiological parameter of tumor perfusion in response to anti-angiogenic therapy of a pancreatic human tumor xenograft that was associated with enhanced radiation response.

Ionizing radiation induces neuroendocrine differentiation of prostate cancer cells in vitro, in vivo and in prostate cancer patients.

Prostate cancer remains the most common noncutaneous cancer among American men. Although most patients can be cured by surgery and radiotherapy, 32,050 patients still died of the disease in 2010. Many patients receive radiotherapy either as a primary therapy, salvage therapy, or in combination with surgery or hormonal therapy. Despite initial treatment, several studies suggest that approximately 10% of low-risk prostate cancer patients and up to 30-60% with more advanced cancer patients experience biochemical recurrence within five years after radiotherapy. Thus, elucidating the molecular mechanisms underlying radioresistance and tumor recurrence has the potential to significantly reduce prostate cancer mortality. We previously demonstrated that fractionated ionizing radiation (IR) can induce the prostate cancer cell line LNCaP to undergo neuroendocrine differentiation (NED) by activation of cAMP response element binding protein (CREB) and cytoplasmic sequestration of ATF2, two CRE-binding transcription factors that oppose each other to regulate NED. Importantly, IR-induced NED is reversible and de-differentiated cells are cross-resistant to IR, androgen depletion and docetaxel treatments. These findings suggest that radiation-induced NED may allow prostate cancer cells to survive treatment and contribute to tumor recurrence. In the present study, we further demonstrated that IR also induces NED in a subset of DU-145 and PC-3 cells. In addition, we confirmed that IR induces NED in LNCaP xenograft tumors in nude mice, and observed that the plasma chro-mogranin A (CgA) level, a biomarker for NED, is increased by 2- to 5-fold in tumor-bearing mice after fractionated radiation doses of 20 and 40 Gy, respectively. Consistent with these in vivo findings, a pilot study in prostate cancer patients showed that the serum CgA level is elevated in 4 out of 9 patients after radiotherapy. Taken together, these findings provide evidence that radiation-induced NED is a general therapeutic response in a subset of prostate cancer patients. Thus, a large scale analysis of radiotherapy-induced NED in prostate cancer patients and its correlation to clinical outcomes will likely provide new insight into the role of NED in prostate cancer radiotherapy and prognosis.

An ultrasonically powered implantable micro-oxygen generator (IMOG).

In this paper, we present an ultrasonically powered implantable micro-oxygen generator (IMOG) that is capable of in situ tumor oxygenation through water electrolysis. Such active mode of oxygen generation is not affected by increased interstitial pressure or abnormal blood vessels that typically limit the systemic delivery of oxygen to hypoxic regions of solid tumors. Wireless ultrasonic powering (2.15 MHz) was employed to increase the penetration depth and eliminate the directional sensitivity associated with magnetic methods. In addition, ultrasonic powering allowed for further reduction in the total size of the implant by eliminating the need for a large area inductor. IMOG has an overall dimension of 1.2 mm × 1.3 mm × 8 mm, small enough to be implanted using a hypodermic needle or a trocar. In vitro and ex vivo experiments showed that IMOG is capable of generating more than 150 µA which, in turn, can create 0.525 µL/min of oxygen through electrolytic disassociation. In vivo experiments in a well-known hypoxic pancreatic tumor models (1 cm (3) in size) also verified adequate in situ tumor oxygenation in less than 10 min.

A simple method for dose fusion from multimodality treatment of prostate cancer: brachytherapy to external beam therapy.

PURPOSE: Suboptimal dosage evaluated from postimplant dosimetry of prostate brachytherapy creates conundrum that needs resolution. This pilot study was undertaken to explore the feasibility of summing and visualizing radiation dosage from multimodality treatment. METHODS AND MATERIALS: Four weeks after (125)I permanent prostate seed implant, CT scans were performed on the whole pelvis of patients using our standard protocol for prostate planning. The acquired CT data sets were reconstructed using different sizes of field of view (FOV). The images with limited FOV focusing on prostate were imported into Variseed (Varian Medical Systems, Inc., Palo Alto, CA) for postimplant evaluation, whereas images with full FOV were imported to Eclipse (Varian Medical Systems, Inc., Palo Alto, CA) treatment planning system (TPS) for future managements, that is, for external beam salvage. RESULTS: The dose matrix resulted from the postimplant dosimetry was exported from Variseed in standard DICOM format and imported into Eclipse TPS. The brachytherapy dose matrix was registered with the patient images with full FOV in Eclipse TPS. Targets for dose boost were defined based on the isodose curves generated from brachytherapy. An external photon beam plan was successfully generated to deliver dose for selected underdose regions. CONCLUSION: Accurate external beam radiation treatment planning can be accomplished using our planning protocols when inadequate brachytherapy dose delivery occurs. The proposed technique can be used to safely deliver additional external radiation dose using intensity-modulated radiation therapy technique after suboptimal brachytherapy procedure.