Top53

TOP-53 (24) is a epipodophyllotoxin derivative with a basic aminoalkyl side chain. This not only improves drug solubility, but is also suggested to confer binding of the drug to phospholipids (especially phosphatidylserine, association constant Ka = 5.6 x 10^6M^ resulting in its selective accumulation in lung tissue. TOP-53 stabilizes topo II-DNA cleavable-complex formation by interfering with the DNA religation activity of the enzyme, with a DNA cleavage site specificity that is identical to that of etoposide.131 It is a potent cytotoxin (IC50 0.07-0.7 mM in a range of murine tumor cell lines), with broad in vivo activity against human tumor xenografts (NL-22 and NL-17 colon cancer, UV2237M fibrosarcoma, and K1735M2 melanoma), especially lung metastases.132 Preliminary conference reports of Phase I trials suggest a maximum tolerated dose of about 110 mgm _ 2, with the major toxicity being leukopenia.

7.05.3.5 Miscellaneous Compounds

XL-119 (NSC 655649) (25) is a more water-soluble (about 4mgmL_ 1 as the HCl salt), monoethylated derivative of the natural antitumor antibiotic rebeccamycin,133 and can be prepared from it by direct alkylation.134 It evolved from a synthesis program aimed at developing analogs with better in vivo distributive properties than rebeccamycin.135 In studies using 14 established cell lines and 20 early-passage clinical isolates of pediatric solid tumors in a growth inhibition assay, XL-119 had IC50 values in the range 0.5-1 mM, similar to plasma levels achieved during adult Phase I clinical trials.136 In Phase I trials, XL-119 showed dose-dependent pharmacokinetics that fitted a three-compartment model, and a long terminal half-life (49 h and 154h in the two studies respectively).137'138 A Phase II study in advanced renal cell cancer patients showed that a dose of 165 mgm_2 daily intravenously for 5 days was well tolerated and had modest antitumor activity, with 8% partial responses and 46% stable disease. The major toxicity was myelosuppres-sion.139 A Phase II trial in patients with minimally treated metastatic colorectal cancer given 500mgm_2 once every 3 weeks showed no activity.140

IST-622 (26) is a semisynthetic analog of the Actinomycete-derived antitumor antibiotic chartreusin, and is a potent topo II inhibitor.141 It has excellent activity in a wide range of in vivo murine tumor models, including Colon 26 and Colon 38 adenocarcinomas, and M5076 reticulum cell sarcoma, and was also active in two of seven human tumor xenografts. In vivo, IST-622 acts as a prodrug, being rapidly metabolized into the exo-benzylidene metabolite A-132 (27) but not into chartreusin.142,143 A Phase I study gave the drug for 5 consecutive days, and derived a maximum tolerated dose of 525-700 mgm _ 2. A follow-up Phase II trial in 18 patients with breast cancer used oral dosing at 280 or 525 mgm_2 once daily for 5 days, and measured the plasma concentrations of the drug and its main metabolites. The major toxicity was myelosuppression, but therapeutic effects were not reported.144

7.05.3.5.3 Elinafide

Elinafide (LU-79553) (28) is a symmetric dimeric bis(naphthalimide),145 and an example of a broader class of compounds comprised of neutral chromophores joined by cationic linker chains.146 Elinafide is reported as a DNA bis-intercalator, suggested to bind via the major groove.147 A nuclear magnetic resonance (NMR) structure of elinafide bound to the oligodeoxynucleotide duplex d(ATGCAT)2 showed that the two naphthalimide chromophores bis-intercalate at the TpG and CpA steps of the DNA. The linker chain lies in the major groove, with the two amino groups H-bonded to the guanine bases. The naphthalimide rings exchange by rotational ring flipping (at 1800 s _ 1 at 36 °C), without affecting the binding of the linker chain region.148 Elinafide proved highly cytotoxic in vitro (IC50 from 2 x 10 _ 7 to 5 x 10 _ 10 M), and very active in a series of human xenograft models in nude mice, achieving complete or partial regressions in LX-1, CX-1 (colon), DLD (colon), and LOX (melanoma) xenografts.149 A Phase I trial of elinafide given intravenously for 5 days every 3 weeks established the maximum tolerated dose as 18mgm_2, with the major toxicity being a cumulative muscular toxicity. The cumulative nature of the principal toxicities suggested that rigorous, long-term toxicological monitoring is required.150 A second Phase I trial also found dose-limiting neuromuscular toxicity,151 which may limit further development.

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