In Vivo Antitumor Activity

Jones, P. et al. (2008) A novel series of potent and selective ketone histone deacetylase inhibitors with antitumor activity in vivo. Journal of Medicinal Chemistry, 51, 2350-2353. 

The first investigations on the antitumor activity in vivo of cyclophosphazenes were started late in 1976 on murine L1210 and P388 leukemias (DBA/2 female mice) and on sub-cutaneous (s.c.) B16 melanoma (C57 black female mice). 

Ovatine (6) and lindheimerine (7) have been isolated (53) for the first time from the bark and leaves of G. ovata var. lindheimeri Torr., a plant that has shown confirmed antitumor activity in vivo. These two new alkaloids are accompanied by the known alkaloid, garryfoline (8), which also occurs in the Mexican tree, G. laurifolia Hartw 34). 

Lindheimerine occurs in extremely small quantity by comparison with ovatine. Since these two alkaloids are closely related chemically, we suggest that lindheimerine may be a biogenetic precursor of ovatine. These alkaloids did not exhibit any antitumor activity in vivo or in vitro. 

The cytotoxic effect and antitumor activity of triethyltin lupinyl sulfide hydrochloride have been investigated133. Different patterns of antiproliferative effects have been observed in a panel of human cell lines in vitro. Acute toxicity at doses of 21 and 17.5 mg kg-1 in mice was reported and disappeared progressively at lower concentrations. On this base, the doses of 3.5, 7 and 14 mgkg-1 were selected to assess the antitumor activity in vivo against the P388 leukemic cells xenografted in mice. This compound was able to induce a dose-dependent significant reduction of tumor volume, up to 46%. 

Alama A, Viale M, Cilli M, Bruzzo C, Novelli F, Tasso B, Sparatore F (2009) In vitro cytotoxic activity of tri- -butyltin(IV)lupinylsulfide hydrogen fumarate (IST-FS 35) and preliminary antitumor activity in vivo. Invest New Drugs 27 124—130... 

A novel pentafluorinated epipodophyUoid characterized by marked antitumor activity in vivo is F11872. It is a dual inhibitor of the cataljdic activity of both topoi-somerases I and II, with markedly superior activity in vivo compared with other dual inhibitors, such as intopli-cin, TAS-103, and others (22). 

The fluorescent complex [Ru(II)(3,4,7,8-tetramethylphen)3]Cl2 is readily taken up by P388 leukemia cells in culture and is visible on the cell surface, in the cytoplasm, and in the nucleus, but it does not exhibit antitumor activity in vivo (11). The platinum complexes [Pt(en)(oxalate)], [Pt(NH3)2(H20)2l (as the dinitrato complex), and [Pt(en)3] + also cause convulsions in animals (12) the latter two complexes are positively charged and relatively inert and the former is neutral and presumably undergoes an activation step before it binds to the neuromuscular junction. Curiously, the related malonato complex is not a neurotoxin. Care is taken in the clinic to administer cisplatin in saline solutions to avoid hydrolysis and minimize the production of neurotoxic aqua or hydroxobridged Pt(II) species. 

The pyrazole- and thiazole analogues of the 3 -deoxy-3 -amino-4 -methoxy Combretastatin A-4 showed potent antimitotic (IC50 3.0 pM and IC50 10 pM) activity. The former showed also a potent cytotoxic activity (IC50 8.4 nM ). Moderate antimitotic activity (IC50 3.0 pM) and weak cytotoxic activity was observed for a triazole derivative, whereas tetrazole ring confers potent antimitotic (ICso 2.0 pM) as well as cytotoxic activity. Compounds with potent cjdotoxicity were further evaluated in vivo in the Colon murine tumor model. The best antitumor activity in vivo, expressed as tumour growth suppression, was observed for the thiazole and tetrazole derivatives with values comparable to the ones observed for 3 -deoxy-3 -amino Combretastatin A-4 hydrochloride. 

Arguello F, Alexander M, Sterry JA, Tudor G, Smith EM, et al. 1998. Flavopiridol induces apoptosis of normal lymphoid cells, causes immunosuppression, and has potent antitumor activity in vivo against human leukemia and lymphoma xenografts. Blood 91 2482-90... 

Two derivatives, compound 94, which bears an esperamicin core with an epoxide trigger, and 95, which is a hybrid between esperamicin and dynemicin A cores,have been reported (Scheme 19.25). Both compounds, after trifluoroacetamide removal, underwent cycloaromatization and showed an interesting antitumor activity in vivo in mice. 

Daphne tangulica Maxim, (roots) Biflavonoids. daphnodorin Di (187) daphnodorin D2 (188). Marked antitumor activity in vivo. Zhang et ah, 2007[343]. 

Kinzel O et al (2009) Discovery of a potent class I selective ketone histone deacetylase inhibitor with antitumor activity in vivo and optimized pharmacokinetic properties. J Med Chem 52(ll) 3453-3456... 

NDGA has been shown to have antitumor activity in vivo and in vitro. It is a powerful cancer antimetabolite producing in vitro complete inhibition of aerobic and anaerobic glycolysis and respiration of suspensions of several types of tumor cells including leukemia types. In vivo, NDGA combined with ascorbic acid is reported to reduce... 

A potent antitumor compound, aplyronine A (64), was first isolated from the sea hare Aplysia kurodai off the Pacific coast of Mie Prefecture, Japan. Aplyronine A (64) exhibited a high degree of antitumor activity in vivo against P388 murine leukemia (77C 545%, 0.08 mg/kg), Lewis lung carcinoma TIC = 556%,... 

C. Pandey et al., J. Amibiol. 34, 1389 (1981). Antimicrobial and cytotoxic activity in vitro and antitumor activity in vivo ... 

The growth inhibition of virus-transformed cells in vitro and antitumor activity in vivo of geldanamycin (85) and its derivatives [230,231], and the inhibition of DNA synthesis in murine tumor cells by 85 were reported [232,233]. Geldanamycin (85) is an antibiotic that preferentially inhibits Gl/S transition and causes G2/M arrest in human leukemia HL-60 cells. Also, it was found that 85 selectively inhibited recombinant Src tyrosine kinase without significantly inhibiting protein kinase A. The perturbation of cell cycling by 85 was accompanied by marked suppression of c-MYC expression [234]. 

Sakamoto I, Tezuka K, Fukae K, Ishii K, Taduru K, Maeda M, Ouchi M, Yoshida K, Nambu Y, Igarashi J, Hayashi N, Tsuji T, Kajihara Y (2012) Chemical synthesis of homogeneous human glycosyl-interferon-beta that exhibits potent antitumor activity in vivo. J Am Chem Soc 134 5428-5431... 

Oehydroascorbic Acid. Oxidation products of ascorbic acid have antitumor activity in vivo. Oehydroascorbic acid (150 mg/kg body weight) and 2,3-diketogulonic acid (115 mg/kg body weight) inhibited growth of solid Sarcoma 180... 

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