Loss of the promyelocytic leukaemia (PML) tumour suppressor has been observed in several human cancers. The tumour-suppressive function of PML has been attributed to its ability to induce growth ...arrest, cellular senescence and apoptosis. Here we identify PML as a critical inhibitor of neoangiogenesis (the formation of new blood vessels) in vivo, in both ischaemic and neoplastic conditions, through the control of protein translation. We demonstrate that in hypoxic conditions PML acts as a negative regulator of the synthesis rate of hypoxia-inducible factor 1alpha (HIF-1alpha) by repressing mammalian target of rapamycin (mTOR). PML physically interacts with mTOR and negatively regulates its association with the small GTPase Rheb by favouring mTOR nuclear accumulation. Notably, Pml-/- cells and tumours display higher sensitivity both in vitro and in vivo to growth inhibition by rapamycin, and lack of PML inversely correlates with phosphorylation of ribosomal protein S6 and tumour angiogenesis in mouse and human tumours. Thus, our findings identify PML as a novel suppressor of mTOR and neoangiogenesis.
Several drug combinations have been designed for the initial treatment of multiple myeloma. Although none has been shown to be superior, a regimen that leads to a high response rate in association ...with low incidence of major adverse events is highly desirable. We report response rates and complications - specifically thromboembolic complications- with the combination of doxorubicin, thalidomide and dexamethasone for patients with Durie-Salmon stage II and III symptomatic multiple myeloma.
Methods: In this regimen, the drugs are used in a sequential fashion with the intent to reduce the high incidence (up to 28%) of venous thromboembolic complications known to be associated with this combination of drugs (NEJM 2001; 344:1951–2; Blood 2001; 98:1614–5; Blood 2002; 100:1168–71). Doxorubicin and dexamethasone (AD; A=9mg/m2/day, Days 1–4; D=40mg/day, Days 1–4, 9–12, 17–20) are given for 3 months followed by thalidomide and dexamethasone (TD; T=200mg nightly; D=as above) for 2 months with prophylactic antibiotics and daily aspirin (81 mg/day). At any point during therapy patients achieving a complete response (immunofixation negative) are permitted to forgo further induction therapy and proceed with autologous stem cell transplantation.
Results: As of 8/04, we have enrolled 38 patients ( 22 men, 16 women) with a median age of 59 years (range, 35–82). Median β2 microglobulin level was 2.5 mg/L (ND-12.5) and median albumin level 3.95 g/dL. Fluorescent in situ hybridization (FISH) studies of baseline bone marrows, searching for abnormalities of chromosomes 11, 13 and 14, are available for 36 patients. Among those, 22 patients have abnormal findings. Three patients have been removed from study, one for a DVT that occurred during cycle 5, one for a myocardial infarction after cycle 1, and one for refusing further therapy. Five patients are currently receiving treatment. Therefore response data are available for 30 patients. Among those, 26 have responded to therapy (86.6 %), including 6 complete responses (20%), 8 very good partial responses (26.6%) and 12 partial responses (40%). Two patients (6.6 %) have stable disease while two patients (6.6 %) have progression of disease. When patients are stratified according to the International Staging System using β2 microglobulin and albumin levels, the response rate is not influenced by stage, as overall response rate is 81% for stage I (n=22), 100% for stage II (n=7) and 100 % for stage III (n=1). Likewise, the presence of Δ13 does not appear to affect overall response rate (82% for patients with no Δ13 and 100 % for patients with Δ13). Among patients who completed the treatment and those removed from study because of DVT, only three developed DVT (3/31; 9.6 %). All other patients tolerated the treatment well and completed therapy with no major adverse event.
Conclusion: These results indicate that the regimen consisting of doxorubicin, dexamethasone, and thalidomide used in a schedule that allows sequential administration of the drugs as described and DVT prophylaxis with low dose aspirin is well tolerated and results in a high response rate with a low incidence of therapy-related thromboembolic complications.
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