Radioimmunotherapy with anti-CD20 monoclonal antibodies is a promising new treatment approach for patients with relapsed B-cell lymphomas. However, the majority of patients treated with conventional radiolabeled anti-CD20 antibodies eventually have a relapse because the low tumor-to-blood and tumor-to-normal organ ratios of absorbed radioactivity limit the dose that can be safely administered without hematopoietic stem cell support. This study assessed the ability of a streptavidin-biotin "pretargeting" approach to improve the biodistribution of radioactivity in mice bearing Ramos lymphoma xenografts. A pretargeted streptavidin-conjugated anti-CD20 1F5 antibody was infused, followed 24 hours later by a biotinylated N-acetylgalactosamine-containing "clearing agent" and finally 3 hours later by 111 In-labeled DOTA-biotin. Tumor-to-blood ratios were 3:1 or more with pretargeting, compared with 0.5:1 or less with conventional 111 In-1F5. Tumorto-normal organ ratios of absorbed radioactivity up to 56:1 were observed with pretargeting, but were 6:1 or less with conventional 111 In-1F5. Therapy experiments demonstrated that 400 Ci (14.8 MBq) or more of conventional 90 Y-1F5 was required to obtain major tumor responses, but this dose was associated with lethal toxicity in 100% of mice. In marked contrast, up to 800 Ci (29.6 MBq) 90 Y-DOTA-biotin could be safely administered by the pretargeting approach with only minor toxicity, and 89% of the mice were cured. These data suggest that anti-CD20 pretargeting shows great promise for improving current therapeutic options for B-cell lymphomas and warrants further preclinical and clinical testing. IntroductionNon-Hodgkin lymphomas afflict 58 000 Americans each year and are rapidly increasing in incidence. 1 Only one third of patients with B-cell lymphoma are cured with conventional chemotherapy and radiotherapy; therefore, innovative new treatments are a high priority for this malignancy. Monoclonal antibodies (mAbs) directed against tumor-associated antigens have emerged as effective new reagents for lymphomas and are being tested extensively in the laboratory and in clinical trials. Although many B-cell surface antigens have been targeted with antibodies, to date anti-CD20 antibodies have been the most widely tested and have achieved the best clinical results. [2][3][4][5] CD20 is a 35 000-kd nonglycosylated phosphoprotein expressed on the surface of nearly all mature B-lymphoid cells and on 95% of B-cell lymphomas. 6 The CD20 antigen appears to have many favorable attributes that commend its use as an immunotherapeutic target. CD20 is not shed into the bloodstream, is not rapidly internalized, and is expressed at a high surface density on the vast majority of lymphomas. 6-8 Rituximab, a chimeric anti-CD20 antibody, induces remissions in 50% to 70% of patients with newly diagnosed follicular lymphomas, 48% to 60% of patients with relapsed follicular lymphomas, 30% to 35% of those with relapsed diffuse large B-cell lymphomas, 30% to 35% of patients with relapsed mantle cell...

Deoxyadenosine 5'-and 3'-dithiophosphate and thymidine 5'-and 3'-dithiophosphate were synthesized. These are the fiist examples of this class of compounds. Although several synthesis strategies were examined, the most successful involved coupling deoxynucleoside H-phosphonodithioates with 9-fluorenemethanol under oxidation conditions to generate deoxynucleoside 9-fluorenemethyl phosphorodithioates. Deprotection by treatment with concentrated ammonium hydroxide followed by HPLC purification yielded the deoxynucleoside dithiophosphates. These analogs showed modest inhibition of avian myeloblastosis virus reverse transcriptase. They failed to inhibit human immunodeficiency virus reverse transcriptase, alkaline phosphatase, T4 polynucleotide kinase, or DNA polymerase I Klenow fragment.

This study included 12 Chinese patients with a wide spectrum of phenotypes of tyrosine hydroxylase deficiency. Seven females and 5 males, aged 2.2 to 41 years, had phenotypes ranging from severe type with onset at infancy to mild type with onset after 3 years of age. Patients with the severe type had encephalopathy with poor treatment response or infantile parkinsonism with motor delay. Patients with the less common mild type had dopa-responsive dystonia or a newly recognized predominant symptom of myopathy. Female siblings had more severe phenotypes. The phenotype and treatment outcomes were strongly related to a homovanillic acid level and homovanillic acid/5-hydroxyindolacetic acid ratio of less than 1 in the cerebrospinal fluid. Hyperprolactinemia was found in 50% of the severe cases. Levodopa was the mainstay of treatment, and early addition of selegiline resulted in a remarkable response in some patients. Treatment response for mild-type patients is universally good even with a treatment delay of 10 years after onset of neurological symptoms.

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