Rubidomycin

History of Rubidomycin.- The First Antimitotic Antibiotics.- Isolation of Rubidomycin.- The First Clinical Trials.- The First Overall Surveys.- I - Preparation and Experimental Investigation.- 1: Preparation.- 1. Production.- a) Productive Strains.- b) Production in Fermenters.- 2. Isolation.- a) Extraction of the Crude Base.- b) Fractionation by Counter-current Distribution.- 3. Analytical Methods.- 4. Physicochemical Properties.- a) Solubility.- b) Stability.- c) Properties.- d) Comparison of Rubidomycin and Rubomycin C on the Basis of their Physicochemical Properties.- 5. Tritiated Rubidomycin.- a) Preparation.- b) Analytical Results.- 2: Structure.- 3: Biological Activity.- 1. Cytostatic Activity and Cell Changes.- a) KB and HeLa Cells.- ?) Cytostatic Activity.- ?) Cell Changes.- b) Ehrlich Ascites Cells.- ?) Cytostatic Activity.- ?) Cell Changes.- c) Plant Cells.- 2. Antitumor Activity in Animals.- a) Tumors of Mice.- ?) Carcinomas.- ?) Ehrlich Ascites Tumor.- ?) Sarcomas.- ?) Leukoses and Leukosarcomatosis.- b) Tumors and Leukemia of Viral Etiology.- ?) Avian Sarcomas.- ?) Shope Fibroma.- ?) Rauscher Leukemia.- 3. Immunodepressive Activity.- a) Effect on the Production of Antibodies.- b) Action on Immunologically Active Spleen Cells.- c) Action on Grafts.- d) Action on the Lymphoblastic Transformation of Lymphocytes in vitro.- 4. Antibacterial Activity.- 5. General Pharmacological Properties.- a) Effect on the Cardiovascular System.- ?) Effect on the Arterial Pressure.- ?) Effect on the Heart.- b) Effect on Respiration.- c) Effect on the Sympathetic Nervous System.- 4: Fixation in the Cell and Mechanism of Action.- 1. Fixation in the Cell.- a) Autoradiography of KB Cells.- b) Measurement of the Tritiated Rubidomycin in Normal Hepatic Cells.- c) Fluorescent Microscopy (KB Cells).- 2. Mechanism of Action.- a) Action on Energy Metabolism.- ?) Method of Study.- ?) Results.- b) Action on Protein Synthesis.- ?) Method of Study.- ?) Results.- c) Action on the Synthesis of Nucleic Acids.- ?) Staining of the Cells with Acridine Orange.- ?) Autoradiographic Study of the Incorporation of Tritiated Thymidine and Uridine into the Treated Cells.- ?) Determination by Measurement of the Incorporation of Tritiated Thymidine and Uridine in the Nucleic Acids of Ehrlich Ascitic Tumor Cells.- 5: Toxicology.- 1. Acute Toxicity and Subacute (5 Days) Toxicity.- a) Method of Study.- b) Results.- ?) Acute Toxicity.- ?) Subacute Toxicity.- 2. Long-term Toxicity (3 Months).- a) Method of Study.- b) Results.- ?) Trials on Rabbits.- ?) Trials on Dogs.- 3. Teratogenic Action.- a) Chick Embryo.- b) Mice.- c) Rabbits.- d) Conclusion.- 4. Carcinogenic Effect.- a) Material and Method.- ?) Subcutaneous Administration.- ?) Oral and Intraperitoneal Administration.- b) Results.- ?) Subcutaneous Administration.- ?) Oral and Intraperitoneal Administration.- c) Conclusion.- II - Clinical and Therapeutic Study.- 6: Posology.- 1. Dosage with Rubidomycin.- 2. Presentation of Rubidomycin.- 3. Route of Administration.- 4. Dosage.- 5. General Management of Treatment. Precautions.- a) Symptomatic Treatment.- b) Place of Treatment.- c) Special Treatment of Hyperleukocytic Forms and Very Active Multiple Drug Therapy.- 6. Symptomatic Treatment.- a) Isolation.- b) Platelet Transfusion.- c) Bacterial Infections.- ?) Antibiotic Treatment before the Stage of Aplasia.- ?) Antibiotic Treatment during the Stage of Aplasia.- ?) Minimum Inhibiting Concentration.- ?) Choice of Antibiotic. Concept of Bactericidal Power.- ?) Antibiotic Combinations.- ?) Problems of Fungal Infections.- ?) Duration of Antibiotic Treatment.- d) Leukocyte Transfusions from Donors with Chronic Myeloid Leukemia at the Myelocytic Stage.- 7: Therapeutic Episodes and Accidents.- 1. Marrow Insufficiency.- a) General Characteristics.- b) Special Characteristics.- 2. Cardiac Complications.- a) Cardiac Complications Observed during and after Lengthy Treatment.- b) Cardiac Complications Observed during Less Prolonged Treatment.- c) Conclusion: Treatment and Attempted Prevention of Cardiac Complications.- 3. Other Complications.- a) Local Complications.- b) Miscellaneous Complications and Accidents.- 8: Treatment of Acute Lymphoblastic Leukemia with Rubidomycin Only.- 1. Preliminary Remarks.- a) Techniques Employed in Hematologic Diagnosis.- b) Definition of Complete Remission.- c) Preliminary Observations.- 2. Dosage.- 3. Study of a First Personal Series.- a) Results.- b) Frequency of Remission.- c) Complete Remission. Chronology, Quantitative Changes.- d) Incomplete Remissions.- e) Partial Failures (11 Cases).- ?) Aplasia without Blast Cells.- ?) Aplasia with Persistance of Blast Cells.- f) Total Failure.- g) Duration of Remissions.- h) Complications Caused by Rubidomycin.- 4. Two Examples of Rubidomycin Used Alone.- 5. Overall Results. Effect of Rubidomycin Alone on the Course of Acute Lymphoblastic Leukemia.- 9: Acute Granulocytic Leukemia. Acute Myeloblastic and Promyelocytic Leukemia.- 1. Preliminary Observations.- 2. Dosage.- 3. Study of a First Personal Series.- a) Patients Treated.- b) Time of Complete Remission.- ?) Average Interval.- ?) Short Interval.- ?) Long Interval.- c) Duration of Complete Remission.- d) Incomplete Remissions.- e) Failures.- 4. General Survey. General Features of the Course of the Disease. Prognosis.- a) Age.- b) Type of Leukemia.- c) Hospital Organization.- d) Experience of the Hematologist.- e) Comparison of our Personal Series with the Results Obtained by Other Workers.- ?) General Causes.- ?) Special Difficulties.- 5. General Indications.- 6. Acute Promyelocytic Leukemias.- 7. Acute Monoblastic Leukemia.- 10: Combination Therapy in the Treatment of Acute Leukemia.- 1. General.- a) The Simultaneous Use, or the Use at Very Short Intervals, of Four Main Drugs.- b) The Sequential or Iterative Method.- c) The Reinduction Method.- 2. Combination Therapy and Properties of Rubidomycin.- 3. Acute Lymphoblastic Leukemia.- a) Use of Rubidomycin, Vincristine, and Prednisone in Combination.- b) Induction Treatment.- c) Maintenance Treatment and Reinductions.- d) Patients Treated.- e) Results.- ?) Overall Results.- ?) Inducement of Complete Remission (117 Cases).- ?) Duration of Remissions.- f) Tolerance.- ?) The Initial Phase.- ?) Adjustment of Therapy.- ?) Tolerance of Reinduction.- g) Conclusion.- h) Treatment of Relapses.- i) Other Trials.- k) Other Combinations Used in Treating Acute Lymphoblastic Leukemia.- 4. Acute Granulocytic Leukemia.- a) Initial Combination of Rubidomycin with Other Drugs.- b) Prolongation of Complete Remission.- 11: Cytological and Immunological Study of Acute Leukemia Treated with Rubidomycin.- 1. Cytological Study.- a) Acute Lymphoblastic Leukemia.- b) Acute Granulocytic Leukemia.- 2. Immunodepressive Power of Rubidomycin.- a) Studies in Animals.- b) Studies in Man.- ?) Effect on the Production of Circulating Antibody.- ?) Effect on Delayed Hypersensitivity Reactions.- 12: Treatment of Chronic Leukemia, Sarcoma, Hodgkin's Disease, and Cancer with Rubidomycin.- 1. Chronic Leukemia.- a) Chronic Myeloid Leukemia.- b) Chronic Lymphoid Leukemia.- 2. Sarcoma of the Hemopoietic Organs.- a) Lymphoblastosarcoma.- ?) Rubidomycin Used Alone.- ?) Rubidomycin Used in Combination with Other Drugs.- ?) Complete Remissions.- ?) Incomplete Remissions.- ?) Failures.- ?) Tolerance.- ?) Discussion.- b) Reticulosarcoma.- 3. Hodgkin's Disease.- 4. Myeloma.- 5. Solid Tumors.- a) Neuroblastoma.- b) Rhabdomyosarcoma.- c) Cancer.- d) Intra-Arterial Route.- Conclusions.- References.