The availability of an i.v. form of busulfan (Bu) has prompted investigation of administration schedules other than the 4-times-daily dosage commonly used with oral Bu. We have studied an allogeneic stem cell transplantation (SCT) preparative regimen comprising fludarabine (FLU) 50 mg/m2 on days -6 to -2 plus i.v. Bu 3.2 mg/kg daily in a 3-hour infusion on days -5 to -2. The regimen was given to 70 patients aged 15 to 64 years (median, 41 years) with hematologic malignancy. Thirty-six patients (51%) had high-risk malignancy, 28 (40%) had unrelated or genotypically mismatched related donors (alternate donors [AD]) and 29 (41%) received bone marrow rather than blood as stem cell source. Acute GVHD prevention comprised antithymocyte globulin 4.5 mg/kg over 3 days pretransplantation, cyclosporin A, and short-course methotrexate with folinic acid. Hepatic toxicity was transient and there was no clinically diagnosed veno-occlusive disease. Grade II stomatitis occurred in 49 patients (70%) and hemorrhagic cystitis in 9 patients (13%). One patient with subtherapeutic phenytoin levels had a convulsion 8 hours after the third i.v. Bu dose, but no other neurotoxicity was apparent. Incidence of acute GVHD grades II to IV was 8% and incidence of grade III-IV was 3%, with no deaths from this cause. Actuarial incidence of chronic GVHD at 2 years is 38%. There were 2 cases of graft failure in unrelated donor BMT recipients, 1 of which was reversed by asecond transplantation. With a median follow-up of 16 months (range, 6-27 months), transplantation-related mortality at 100 days and 2 years was 2% and 5% for matched related donor (MRD) SCT and 8% and 19% for AD SCT, respectively (P = not significant). Relapse rates were 21% for 34 patients with acute myeloid leukemia (AML) in complete remission or chronic myeloid leukemia in chronic phase (low-risk), 66% for 19 patients with high-risk AML, and 18% for 17 patients with other active malignancy. Projected disease-free and overall survival rates at 2 years were 74% and 88% for low-risk disease, 26% and 37% for advanced AML, and 65% and 71% for other high-risk disease, respectively. Pharmacokinetic studies were done using 11 samples with the first and fourth doses of Bu. Kinetics were linear, and for the first and fourth doses, the half-lives were 2.60 +/- 0.44 and 2.57 +/- 0.36 hours, respectively. Clearances were 106.77 +/- 16.68 and 106.86 +/- 21.57 mL/min per m2, peak concentrations (Cmax) were 3.92 +/- 0.31 and 3.96 +/- 0.28 mcg/mL, and Bu areas under the plasma concentration versus time curve (AUC) were 4866.51 +/- 771.42 and 4980 +/- 882.80 microM x min, respectively. Bu was completely cleared within 24 hours and the day 4 pharmacokinetic values were very similar to those on day 1 for every patient. The cumulative AUC was comparable to the target range established for p.o. Bu. This regimen incorporating once-daily i.v. Bu is convenient to give, is relatively well tolerated, gives predictable blood levels, and deserves further study in circumstances in which cytoreduction as wel...

Reovirus has potent activity against human malignant gliomas in vitro, in vivo, and ex vivo. Oncolysis with reovirus may be a potentially useful treatment for a broad range of human cancers.

Matrix metalloproteinases (MMPs) have been implicated as important factors in gliomas since they may both facilitate invasion into the surrounding brain and participate in neovascularization. We have tested the hypothesis that deregulated expression of gelatinase-A or B, or an activator of gelatinase-A, MT1-MMP, may contribute directly to human gliomas by quantifying the expression of these MMPs in 46 brain tumour specimens and seven control tissues. Quantitative RT-PCR and gelatin zymography showed that gelatinase-A in glioma specimens was higher than in normal tissue; these were significantly elevated in low grade gliomas and remained elevated in GBMs. Gelatinase-B transcript and activity levels were also higher than in normal brain and more strongly correlated with tumour grade. We did not see a close relationship between the levels of expression of MT1-MMP mRNA and amounts of activated gelatinase-A. In situ hybridization localized gelatinase-A and MT1-MMP transcripts to normal neuronal and glia, malignant glioma cells and blood vessels. In contrast, gelatinase-B showed a more restricted pattern of expression; it was strongly expressed in blood vessels at proliferating margins, as well as tumour cells in some cases. These data suggest that gelatinase-A, -B and MT1-MMP are important in the pathophysiology of human gliomas. The primary role of gelatinase-B may lie in remodelling associated with neovascularization, whereas gelatinase-A and MT1-MMP may be involved in both glial invasion and angiogenesis. © 1999 Cancer Research Campaign

Because pretransplantation anti-thymocyte globulin (ATG) seems to reduce graft-versus-host-disease (GVHD) and treatment-related mortality (TRM) after unrelated donor bone marrow transplantation (BMT), we investigated this agent in matched related donor (MRD) blood cell transplantation (BCT). Fifty-four adults receiving rabbit ATG, cyclosporine A, and methotrexate with myeloablative conditioning and undergoing first MRD BCT were matched for disease and stage with 54 patients not given ATG. Most ATG-treated patients had fludarabine with oral (7) or i.v. busulfan (46) with total body irradiation (TBI) in 10. Control patients largely received TBI with VP16 (28) or oral busulfan with cyclophosphamide (15) or fludarabine (7). The ATG was given at a total dose of 4.5 mg/kg over 3 d, finishing on day 0. Rates of acute GVHD (aGVHD) grade II-IV, aGVHD grade III-IV, and chronic GVHD (cGVHD) were 19 +/- 5% versus 32 +/- 6% (P = .1), 6 +/- 3% versus 13 +/- 5% (P = NS), and 55 +/- 8% versus 96 +/- 3% (P = .002) in the ATG and control groups, respectively. Patients given ATG had fewer sites involved by cGVHD compared with the control group (mean 2.1 +/- 0.2 versus 2.8 +/- 0.2, P = .04). Non-relapse mortality (NRM) with and without ATG, respectively, was 4 +/- 3% versus 17 +/- 5% at 100 d and 9 +/- 4% versus 34 +/- 7% at 4 yr (P = .002). Deaths were GVHD related in 3 ATG-treated patients versus 14 controls (P = .007). Despite a trend to more relapse with ATG (43 +/- 7% versus 22 +/- 7% at 4 yr, P = 0.05), survival was 66 +/- 7% in the patients given ATG versus 50 +/- 7% in the controls (P = 0.046). This study indicates that myeloablative regimens incorporating fludarabine and oral or i.v. busulfan with pretransplantation ATG given to recipients undergoing MRD BCT may result in less cGVHD, lower TRM, and probably improved quality of life in survivors compared with previous protocols.