Intramedullary multiple myeloma is a plasma cell malignancy with a low response rate to therapy and frequent relapse (3
). Sustained response to therapy has been considered to be an important prerequisite for prolonged overall survival in multiple myeloma patients (29
). In the present study, we demonstrated in the SCID-rab mouse multiple myeloma model that fractionated irradiation combined with the anti-angiogenic reagent anginex not only repressed in vivo
BN myeloma cell growth throughout the treatment period but also delayed relapse after treatment. Although the sample size in the present study is small, our use of multiple parameters for tumor growth monitoring in combination with longitudinal observations strengthens the findings. These results indicate the potential therapeutic value of the combined treatment.
Radiotherapy is an effective tumor control modality, and DNA damage induced in tumor cells by radiation is the classical mechanism through which radiotherapy exerts its tumor suppression effects (17
). In the presence of normal oxygen level, a great portion of the damaged DNA becomes unrepairable due to the formation of oxidized side groups of the DNA helix. Under hypoxic conditions, which are often seen in solid tumors, expression of DNA base excision repair proteins such as AP endonuclease (Ape1) are up-regulated (31
) and cell survival factors such as Akt are activated (32
), partially through the redox control of transactivation activities of hypoxia-inducible factor (HIF)-1alpha (33
). These changes result in improved DNA repair capacity and decreased radiosensitivity. Our demonstration of consistent, albeit modest, efficacy of radiation alone in delaying BN tumor growth in vivo
during the treatment period suggests that radiotherapy might not markedly affect the hypoxic status in the tumor microenvironment in this model. It has been noted that the microenvironment of multiple myeloma host tissue, i.e. the bone marrow, is highly hypoxic (34
) and that the growth of intramedullary multiple myeloma is associated with decreased hypoxia (35
) at least in part through increasing angiogenesis in the course of multiple myeloma progression (20
). If this is also true for the SCID-rab mouse multiple myeloma model, the development of the otherwise radiation-induced hypoxia might be offset by the intrinsic angiogenic tendency in the BN tumor and might thus play a lesser role in radiation response. Whether tumor growth in bone grafts is accompanied by increased angiogenesis and whether radiation suppression of tumor growth is associated with significant changes in tumor hypoxia status require further investigation.
To overcome tumor resistance to radiotherapy, various radiosensitization strategies have been developed. Because increased angiogenesis accompanies the progression of intramedullary myeloma (20
), new treatments targeting multiple myeloma vasculature have evolved (37
). Our demonstration of enhancement of the radiation response by anginex indicates that preirradiation targeting of endothelial cells induces robust radiosensitivity in our multiple myeloma model. This is consistent with recent reports demonstrating that radiation-induced damage to endothelial cells and tumor vasculature was a key element leading to tumor growth delay after radiotherapy and can be independent of tumor oxygenation (18
The bone microenvironment plays a pivotal role in the progression of multiple myeloma. On the one hand, multiple myeloma cells stimulate the formation and activity of osteoclasts to resorb the host bone, which in turn releases growth factors and matrix proteins that have stimulatory effects on multiple myeloma. On the other hand, multiple myeloma cells suppress the proliferation and differentiation of osteoblasts, resulting not only in imbalanced bone formation and bone resorption but more importantly in the loss of osteoblast-derived molecules (e.g. osteoprotegerin) inhibitory to osteoclasts and multiple myeloma cells (39
). Osteolysis (either microscopic or radiographic) is an indicator of accelerated multiple myeloma progression as well as poor prognosis (2
). Consistent with these clinical observations, we demonstrated here that the successful suppression of BN tumor growth by the combined therapy was accompanied by a remarkable preservation of the bone structure in the grafts and early inhibition of osteoclast formation/activity. However, we were unable to determine whether the preservation of the bone grafts was the result of the decreased osteolytic signals from the suppressed BN cells or whether the preserved bone and bone cells were instrumental in allowing the combined therapy to induce regression of multiple myeloma. Regardless of the sequence of the events, once-weekly fractionated irradiation in combination with the novel anti-angiogenic agent anginex appears to be a skeleton-sparing modality for intramedullary multiple myeloma.
Despite the robust response of the BN tumor to the combined therapy during the treatment period and a remarkable delay in tumor relapse 4 weeks after the end of treatment, tumor growth eventually resumed, although on a much smaller scale compared with that in the other two treatment groups. In the clinic, the success of multiple myeloma treatment not only is measured by the tumor response to treatment but also is determined by the reduction of the number of multiple myeloma cells that are resistant to the therapy. These therapyresistant cells could be a subpopulation of the multiple myeloma cells with a unique genetic composition that renders them more resistant (40
). They might also arise from the parental cell pool as a consequence of treatment-induced transformation (42
). In addition, the tumor stem cell theory in the context of the development of multiple myeloma has drawn increasing attention (43
) and has provided an alternative explanation for multiple myeloma relapse. These theories, however, leave many critical questions unanswered. For instance, how do these cells behave among the untreated, rapidly proliferating tumor cells? If they are resistant to treatment, do these cells contribute to tumor growth during treatment the same way as they would in the event of relapse? Does the treatmentinduced tumor regression signal these cells to accelerate their proliferation activity? Answers to these questions may facilitate the development of more effective treatment strategies for multiple myeloma by targeting specific cell types.
The low response rate to therapy and early recurrence are two major factors contributing to the poor prognosis of multiple myeloma patients (3
). We present here compelling evidence that localized radiotherapy, when primed with an angiogenesis inhibitor, anginex, is potent in delaying focal BN tumor growth as well as tumor relapse in a mouse model. Our findings demonstrate the possibility of treating localized multiple myeloma of early stage with less cytotoxic but more effective therapies. With the recent demonstration of the feasibility of using helical tomotherapy to deliver total bone marrow irradiation to multiple myeloma patients (45
), the application of radiotherapy in multiple myeloma management is in a stage of resurrection. The efficacy of local radiotherapy (tomotherapy) combined with strategies targeting angiogenic processes warrants further evaluation both in animal models of multiple myeloma and in multiple myeloma patients.