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Supplementary Figures 1-2 from Contribution of Granulocyte Colony-Stimulating Factor to the Acute Mobilization of Endothelial Precursor Cells by Vascular Disrupting Agents

Supplementary Methods from Contribution of Granulocyte Colony-Stimulating Factor to the Acute Mobilization of Endothelial Precursor Cells by Vascular Disrupting Agents

Background/Aim: The occurrence of germ cell tumour (GCT) in the elderly is rare, with scarce data available. The aim of this study was to understand the clinical outcomes of patients with GCT in patients aged > 45 years. Materials and Methods: A retrospective study was conducted in a large tertiary cancer centre in north-west London. Between 1 January 2003 and 31 March 2022, 108 cases of GCT in men aged > 45 years were identified and treated at the Mount Vernon Cancer Centre. The median age at diagnosis was 54 years (range = 45–70 years). Results: The 5-year survival rate of all patients was 96%, and the toxicity profile was similar to the younger age group. Conclusion: Older patients with GCT are able to tolerate chemotherapy; however, care must be taken to prevent life-threatening complications using appropriate dose modification.

Vascular disrupting agents (VDA) cause acute shutdown of abnormal established tumor vasculature, followed by massive intratumoral hypoxia and necrosis. However, a viable rim of tumor tissue invariably remains from which tumor regrowth rapidly resumes. We have recently shown that an acute systemic mobilization and homing of bone marrow–derived circulating endothelial precursor (CEP) cells could promote tumor regrowth following treatment with either a VDA or certain chemotherapy drugs. The molecular mediators of this systemic reactive host process are unknown. Here, we show that following treatment of mice with OXi-4503, a second-generation potent prodrug derivative of combretastatin-A4 phosphate, rapid increases in circulating plasma vascular endothelial growth factor, stromal derived factor-1 (SDF-1), and granulocyte colony-stimulating factor (G-CSF) levels are detected. With the aim of determining whether G-CSF is involved in VDA-induced CEP mobilization, mutant G-CSF-R−/− mice were treated with OXi-4503. We found that as opposed to wild-type controls, G-CSF-R−/− mice failed to mobilize CEPs or show induction of SDF-1 plasma levels. Furthermore, Lewis lung carcinomas grown in such mice treated with OXi-4503 showed greater levels of necrosis compared with tumors treated in wild-type mice. Evidence for rapid elevations in circulating plasma G-CSF, vascular endothelial growth factor, and SDF-1 were also observed in patients with VDA (combretastatin-A4 phosphate)-treated cancer. These results highlight the possible effect of drug-induced G-CSF on tumor regrowth following certain cytotoxic drug therapies, in this case using a VDA, and hence G-CSF as a possible therapeutic target. [Cancer Res 2009;69(19):7524–8]

Background: Interrupting tumour blood flow and delivery of nutrients to cause tumour death is the aim of antiangiogenic and vascular disrupting agents (VDAs). ASA404 is the first VDA to enter Phase III trials. Objective: We review the preclinical and clinical data on this interesting agent and consider its place in modern therapeutics. Methods: PubMed database was searched for ‘ASA404’, ‘AS1404’, ‘DMXAA’, ‘vascular disrupting agents’, ‘ASA404 clinical trials’, ‘AS1404 clinical trials’, ‘DMXAA clinical trials’. Results/conclusions: ASA404 is a tumour VDA that is well tolerated and has shown promise in the treatment of NSCLC in combination with paclitaxel and carboplatin. A confirmatory Phase III trial is currently ongoing.

Nine men and one woman with brain metastases from nonseminomatous germ cell tumors have been treated between 1977 and 1984. All the men had lung metastases. Nine patients had elevated serum values of human chorionic gonadotrophin (HCG), the level was greater than 40,000 IU/I in seven. They were treated with sequential combination chemotherapy either POMB/ACE or EP/OMB in which the methotrexate was given at a dose of 1 g/m2 and intrathecal methotrexate was given during courses not containing intravenous methotrexate. Eight of ten patients are alive, off treatment with no evidence of active disease, of whom five have been in remission and off treatment for more than 18 months. Two patients with primary intracranial nonseminomatous germ cell tumors were treated in a similar fashion. One patient died from enlargement of differentiated teratoma; the other is alive 9+ months off treatment with no evidence of disease. These results, which are better than any previously reported, indicate that chemotherapy is the preferred treatment of primary or metastatic nonseminomatous germ cell tumors of the brain and that only rarely will these patients benefit from surgery or radiotherapy.