Despite the high doses of radiation delivered in the treatment of patients with glioblastoma multiforme (GBM), the tumors invariably recur within the irradiation field, resulting in a low cure rate. Understanding the mechanism of such recurrence is therefore important. Here we have shown in an intracranial GBM xenograft model that irradiation induces recruitment of bone marrow-derived cells (BMDCs) into the tumors, restoring the radiation-damaged vasculature by vasculogenesis and thereby allowing the growth of surviving tumor cells. BMDC influx was initiated by induction of HIF-1 in the irradiated tumors, and blocking this influx prevented tumor recurrence. Previous studies have indicated that BMDCs are recruited to tumors in part through the interaction between the HIF-1-dependent stromal cell-derived factor-1 (SDF-1) and its receptor, CXCR4. Pharmacologic inhibition of HIF-1 or of the SDF-1/CXCR4 interaction prevented the influx of BMDCs, primarily CD11b+ myelomonocytes, and the postirradiation development of functional tumor vasculature, resulting in abrogation of tumor regrowth. Similar results were found using neutralizing antibodies against CXCR4. Our data therefore suggest a novel approach for the treatment of GBM: in addition to radiotherapy, the vasculogenesis pathway needs to be blocked, and this can be accomplished using the clinically approved drug AMD3100, a small molecule inhibitor of SDF-1/CXCR4 interactions.

/pdf/inhibition-of-vasculogenesis-but-not-angiogenesis-prevents-243i0vzo6t.pdf

Inhibition of vasculogenesis, but not angiogenesis, prevents the recurrence of glioblastoma after irradiation in mice

The molecules described herein as antiangiogenic agents and antimetastatic agents represent a wide variety of molecular structures with a wide variety of biological effects and targets. Most often these agents have been generally classified as antiangiogenic or antimetastatic by their effects in an in vitro bio-assay system. The diversity in this group of molecules gives strength to the potential of this approach in therapeutic applications. The biological and biochemical pathways involved in angiogenesis are numerous and redundant. It is likely that there are many angiogenic factors and many pathways of invasion, therefore it is likely that blockade of more than one pathway related to angiogenesis and/or invasion will be necessary to impact on the natural progress of a malignant disease. The vasculature forms the first barrier to penetration of molecules into tumors. Although the antiangiogenic agent treatments administered in this study did not inhibit angiogenesis in these tumors completely, the vasculature present in the treated tumors may be impaired compared to control tumors. Overall, therefore, the best speculation is that the main targets for the antiangiogenic agents are extracellular matrix processes and/or tumor endothelial cells and that inhibition and/or impairment of these non-malignant functions can improve therapeutic responses when used in combination with cytotoxic therapies. The incorporation of antiangiogenic agents and/or antimetastatic agents into therapeutic regimens represents an important challenge. The successful treatment of cancer requires the eradication of all malignant cells and therefore treatment with cytotoxic therapies. The compatibility of antiangiogenic therapy and/or anti-invasion agents with cytotoxic chemotherapeutic agents is not obvious [316]. The goal of the addition of any non-cytotoxic potentiator to a therapeutic regimen is to take a good therapy and, without additional toxicity, ‘push’ it to cure. Cyclophosphamide is a good drug against the Lewis lung carcinoma although no long-term survivors of animals bearing Lewis lung carcinoma are achieved with cyclophosphamide treatment alone. Adding antiangiogenic agents to treatment of this tumor with cyclophosphamide produced a cure rate of 40–50%, meaning that both the primary and metastatic disease has been eradicated in these animals. Cures were achieved only when the antiangiogenic treatments extended from days 4–18 post Lewis lung tumor implantation. The results obtained with the addition of antiangiogenic agents to cytotoxic anticancer therapies in in vivo models of established solid tumors have been very positive and provide direction for future clinical trials including these antiangiogenic agents. Two conclusions may be drawn. First, combinations of antiangiogenic and/or antimetastatic agents evoke a greater effect on tumor response to therapy than does treatment with single agents of these classes. Second, treatment with antiangiogenic agents and/or antimetastatic agents can interact in a positive way with cytotoxic therapies.

A systems approach to cancer therapy. (Antioncogenics + standard cytotoxics-->mechanism(s) of interaction).

The objective of the present study was to evaluate the antitumor effect of a defective adenovirus expressing a secretable angiostatin-like molecule (AdK3) in combination with radiotherapy in rat C6 gliomas s.c. preestablished into athymic mice. In vitro, the combination regimen was significantly (P < 0.001) more cytotoxic for human microcapillary endothelial cells than either treatment alone, whereas survival of C6 glioma cells was not affected in the conditions used. Radiotherapy and AdK3 gene delivery was then studied on well established C6 xenografts (165 +/- 70 mm(3)). In these tumors, AdK3 intratumoral injections had only a marginal effect. Interestingly, when experimental radiotherapy was added, significantly higher (P < 0.005), and possibly synergistic, antitumoral effects were observed that tightly correlated a marked decrease of intratumoral vascularization. The combination of radiotherapy and AdK3 intratumoral injections also revealed a significant (P < 0.05) inhibition of tumor growth as compared with either treatment alone for larger tumors (467 +/- 120 mm(3)). Altogether, these data emphasize the potential of combining a destructive strategy directed against the tumor cells with an anti-angiogenic approach to fight cancer.

https://www.pnas.org/content/pnas/97/12/6698.full.pdf

Combined effects of radiotherapy and angiostatin gene therapy in glioma tumor model

Objective Patients with and without radiation treatment before their breast reconstruction were compared to study the relationship of radiation to flap-related complications. Summary Background Data The transverse rectus abdominis muscle (TRAM) flap for breast reconstruction involves a a vascular pedicle and recipient bed, both included in the radiated field of patients undergoing adjunctive therapy. Detailed reviews of flap-related complications in this subgroup of patients have been limited. Methods One hundred eight patients with radiation treatment who subsequently underwent a TRAM flap breast reconstruction were compared with 572 patients with no radiation treatment before similar reconstruction. Flap-related complications, radiation dosage, time, fields, relationships between risk factors, and complications were studied. Results Overall complication rates were comparable between the two groups. Only fat necrosis (>10% of total reconstruction) was found to be statistically significant (17.6% vs. 10.1%, p = 0.03228). No difference was found for fat necrosis in unipedicled vs. bipedicled flaps controlled for radiation (17.7% vs. 17.4%). Obesity and radiation therapy were associated with fat necrosis and major infection in a logistic regression. Significant abdominal scarring was also associated with major infection (p = 0.0044). Conclusions In this, the largest reported series, radiation therapy was associated with increased fat necrosis and major infection. The use of the TRAM flap was not found to be prohibitive in radiated patients and should still be the first choice in this subgroup of patients.

TRAM flap breast reconstruction after radiation treatment.

The study of angiogenesis in malignant tumors has a long history of more than 200 years. Formal modern studies of tumor angiogenesis and the search for therapeutic antiangiogenic agents have progressed very rapidly over the past 30 years. First generation antiangiogenic agents were very important because they allowed the opportunity to validate the concepts that blocking angigoegenesis could be therapeutically important in cancer and that a role could be found for such molecules in combination therapeutic regimens for cancer. Through the 1970s and 1980s, investigators faced a dilemma regarding how to incorporate agents that “choked-off” the tumor blood supply into multi-component therapeutic regimens that had been developed empirically over many years. TNP470, a synthetic molecule derived from a fungal toxin, and minocycline, a tetracycline, were very useful in the preclinical studies that demonstrated that antiangiogenic therapy could enhance the activity to cytotoxic chemostherapy and radiation therapy. These fisrt generation molecules failed to reach clinical approval, but very quickly antiangiogenic kinase inhibitor and antiangiogenic antibodies, especially bevacizumab, demonstrated very similar effects in preclinical models and entered clinical trial. Returning to early observations, cytotoxic therapies administered in continuous low dose regimens can take best advantage of the toxicity of these molecules toward endothelial cells in ‘metronomic’ regimens. Most recently, large genomics efforts have been devoted to identifying differences between normal endothelium and tumor endothelium with a goal to define highly selective tumor endothelial targets for therapeutic attack. The antiangiogenic therapies that have become approved drugs are administered to patients as important components for combination tereatment regimens.

Combination of Antiangiogenic Therapy with Other Anticancer Therapies

We have evaluated the effect of X irradiation on the mesenchymal tissue growth (blood capillaries and stromal cells) in an angiogenesis system in the mouse. This was accomplished by implanting a polyvinyl alcohol sponge disc in the subcutis of the thorax, and quantifying the extent of growth reduction of capillaries and stromal cells following graded doses of X rays. The sponge disc contained a centrally located pellet impregnated with 20 micrograms of epidermal growth factor and coated with a thin film of slow-releasing compound. Total growth of vessels and fibroblasts was determined by morphometric analysis of histologic sections. The incorporation of ({sup 3}H)TdR was measured during a 24-h period. A dose-response relationship was observed when X irradiation was given on Day 11 after implantation, with the disc removed on Day 20. A single dose of 15 Gy reduced both the rate of incorporation of ({sup 3}H)TdR and the total growth area. These and previous observations point to endothelial cells as important targets of ionizing radiation in the stroma, especially during the period of active proliferation of these cells, induced by growth factors.

Effects of X irradiation on angiogenesis.

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Effects of X irradiation on angiogenesis.