      Document 0099
 DOCN  DRG0099
 UNIQUE IDENTIFIER        DRG-0148
 NAME OF SUBSTANCE        TNP-470 [AmFAR Tx Dir 1995;7(4)]
 REGISTRY NUMBER          129298-91-5
 STANDARD CHEMICAL NAME   (3R,4S,5S,6R)-5-methoxy-4-
                          [(2R,3R)-2-methyl-3-(3-methyl-2-butenyl)
                          -oxiranyl]-1-oxaspiro
                          [2,5]oct-6-yl(chloroacetyl) carbamate [J
                          Pharmacol Exp Ther 1993 Jan;264(1)]
 SYNONYMS                 AGM 1470 [CHEMLINE]
 SYNONYMS                 O-(chloroacetylcarbamoyl) fumagillol [MeSH]
 SYNONYMS                 AGM-1470 [MeSH]
 SYNONYMS                 5-methoxy-4-(2-methyl-3-(3-methyl-2-butenyl)o-
                          xiranyl)-1-oxaspiro(2,5)oct-6-yl(chloroacetyl-
                          )carbamate [MeSH]
 PROTOCOL ID NUMBERS      NCI 92 C-228
 PROTOCOL ID NUMBERS      NIAIAD ACTG 215
 SECONDARY SOURCE ID      DRG
 PHARMACOLOGICAL ACTION   MODE OF ACTION: The angioinhibitory action of
                          TNP-470 involves suppression of mRNA
                          expression of specific members of cdks and
                          cyclins and of activation of both cdc2 and
                          cdk2 kinases in endothelial cells. Inhibits
                          angiogenesis. Angiogenesis is a fundamental
                          process by which new blood vessels are
                          formed. Progressive tumor growth necessitates
                          the continuous induction of new capillary
                          blood vessels which converge upon the tumor.
                          Suppression of tumor growth can be
                          accomplished with the use of antiangiogenesis
                          agents. [AmFAR Tx Dir 1995;7(4)] [J Pediatr
                          Surg 1993 Mar;28(3)] [Cancer Res 1994 Jul
                          1;54(13)]
 DISEASES STUDIED/TREATED Under investigation for the treatment of
                          Kaposi's sarcoma [AmFAR Tx Dir 1995;7(4)]
 CLASSIFICATION CODE      Antineoplastic [AmFAR Tx Dir 1995;7(4)]
 OTHER MAJOR USES         Solid tumors [AmFAR Tx Dir 1995;7(4)]
 SUBSTANCE INTERACTIONS   Possible interaction with steroids, NSAIDS,
                          anticoagulants, or any other agent that may
                          exacerbate bleeding. [NCI 92 C-228]
 ADVERSE EFFECTS          Adverse effects include anorexia; anemia;
                          thrombocytopenia; neutropenia; seizures;
                          ataxia; small focal hemorrhage in lung,
                          retina, and brain (at very high doses);
                          abnormal liver function tests; increased CPK;
                          minimally increased APTT; rash to penicillin;
                          confusion; atrial fibrillation; and
                          anaphylaxis. [NCI 92 C-228; NIAID ACTG 215]
 CONTRAINDICATIONS        Contraindicated in persons with
                          hypersensitivity to TNP-470, fumagillin,
                          cyclodextrin, or other related compounds.
                          [NCI 92 C-228]
 CHEMICAL/PHYSICAL DATA   DRUG DESCRIPTION: Analog of fumagillin (a
                          naturally secreted antibiotic of Aspergillus
                          fumigatus fresenius) [AmFAR Tx Dir 1995;7(4)]
 CHEMICAL/PHYSICAL DATA   MOLECULAR FORMULA: C19H28ClNO6 [CHEMLINE]
 SUBSTANCE DELIVERY DATA  MODE OF DELIVERY: Intravenous. [NCI 92 C-228]
 MANUFACTURERS            National Cancer Institute Adult Intramural
                          Studies
 REFERENCES               Krown SE. AIDS-related Kaposi's sarcoma:
                          clinical aspects (Meeting abstract). Proc
                          Annu Meet Am Assoc Cancer Res; 35:659-60
                          1994.
 REFERENCES               Pluda JM, Wyvill K, Figg WD, Whitcup SM,
                          Lietzau J, Saville MW, Cohen R, Feigal E,
                          Parks D, Foli A, et al. A Phase I study of an
                          angiogenesis inhibitor TNP-470 (AGM-1470),
                          administered to patients (pts) with
                          HIV-associated Kaposi's sarcoma (KS) (Meeting
                          abstract). Proc Annu Meet Am Soc Clin Oncol;
                          13:A8 1994.
 REFERENCES               Takechi A, Uozimi T, Kawamoto K, Ito A,
                          Kurisu K, Sudo K. Inhibitory effect of
                          TNP-470, a new anti-angiogenic agent, on the
                          estrogen induced rat pituitary tumors.
                          Anticancer Res 1994 Jan-Feb;14(1A):157-62.
 REFERENCES               Wilson JT, Penar PL. The effect of AGM-1470
                          in an improved intracranial 9L gliosarcoma
                          rat model. Neurol Res 1994 Apr;16(2):121-4.
 REFERENCES               Pluda JM, Wyvill K, Lietzau J, Figg D,
                          Saville MW, Nguyen BY, Foli A, Bailey J,
                          Cooper M. A phase I trial of TNP-470
                          (AGM-1470) administered to patients with
                          HIV-associated kaposi's sarcoma (KS). Natl
                          Conf Hum Retroviruses Relat Infect (1st).
                          1993 Dec 12-16;:61.
 REFERENCES               Brem H, Folkman J. Analysis of experimental
                          antiangiogenic therapy. J Pediatr Surg 1993
                          Mar;28(3):445-50; discussion 450-1.
 REFERENCES               Takamiya Y, Friedlander RM, Brem H, Malick A,
                          Martuza RL. Inhibition of angiogenesis and
                          growth of human nerve-sheath tumors by
                          AGM-1470. J Neurosurg 1993 Mar;78(3):470-6.
 REFERENCES               Brem H, Gresser I, Grosfeld J, Folkman J. The
                          combination of antiangiogenic agents to
                          inhibit primary tumor growth and metastasis.
                          J Pediatr Surg 1993 Oct;28(10):1253-7.
 REFERENCES               Schoof DD, Obando JA, Cusack JC Jr,
                          Goedegebuure PS, Brem H, Eberlein TJ. The
                          influence of angiogenesis inhibitor AGM-1470
                          on immune system status and tumor growth in
                          vitro. Int J Cancer 1993 Oct 21;55(4):630-5.
 REFERENCES               Kusaka M, Sudo K, Fujita T, Marui S, et al.
                          Potent anti-angiogenic action of AGM-1470:
                          comparison to the fumagillin parent. Biochem
                          Biophys Res Commun 1991 Feb 14;174(3):1070-6.
 ENTRY MONTH              9210
 LAST REVISION DATE       960307
 

SOURCE: National Library of Medicine, Bethesda, MD.  Distributed by AEGIS.
