The potent antitumor agent dolastatin 10 (1) was originally isolated from the sea hare Dolabella auricularia, and we now report its isolation from the marine cyanobacterium Symploca sp. VP642 from Palau. The chemically related analogue symplostatin 1 (2) has been reisolated from Guamanian and Hawaiian varieties of S. hydnoides and its total stereochemistry completed by determining the N,N-dimethylisoleucine unit to be L. Symplostatin 1 (2), like dolastatin 10 (1), is a potent microtubule inhibitor. The antitumor activity of 2 was assessed in vivo against several murine tumors. Symplostatin 1 (2) was effective against a drug-insensitive mammary tumor and a drug-insensitive colon tumor; however, it was only slightly effective against two MDR tumors.

Apratoxin A (1), a potent cytotoxin with a novel skeleton, has been isolated from the marine cyanobacterium Lyngbya majuscula Harvey ex Gomont. This cyclodepsipeptide of mixed peptide-polyketide biogenesis bears a thiazoline ring flanked by polyketide portions, one of which possesses an unusual methylation pattern. Its gross structure has been elucidated by spectral analysis, including various 2D NMR techniques. The absolute configurations of the amino acid-derived units were determined by chiral HPLC analysis of hydrolysis products. The relative stereochemistry of the new dihydroxylated fatty acid unit, 3,7-dihydroxy-2,5,8,8-tetramethylnonanoic acid, was elucidated by successful application of the J-based configuration analysis originally developed for acyclic organic compounds using carbon-proton spin-coupling constants ((2,3)J(C,H)) and proton-proton spin-coupling constants ((3)J(H,H)); its absolute stereochemistry was established by Mosher analysis. The conformation of 1 in solution was mimicked by molecular modeling, employing a combination of distance geometry and restrained molecular dynamics. Apratoxin A (1) possesses IC(50) values for in vitro cytotoxicity against human tumor cell lines ranging from 0.36 to 0.52 nM; however, it was only marginally active in vivo against a colon tumor and ineffective against a mammary tumor.

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The marine sponge Diacarnus cf. spinopoculum has provided a series of norterpenes, including five new compounds (7-11), two new ent-compounds [(-)-1a and (+)-1b], and three known compounds (2a, 2b, and 12). Eight of these compounds represent additional examples of the muqubilin/sigmosceptrellin classes (norsesterterpene peroxides) or the nuapapuin class (norditerpene peroxides). Also isolated were dinorditerpenones 11 and 12, which are biosynthetically related to the muqubilin/sigmosceptrellin structure classes. In all, 11 compounds were evaluated for their cytotoxic properties using a soft agar assay system and the NCI's 60 cell-line screen. Compounds without peroxide functionality were inactive. Overall, the norsesterterpene peroxides were less selective as cytotoxins than norditerpene peroxide analogues. Two compounds, nuapapuin A methyl ester (3) and nuapapuin B (7), which were somewhat selective in their cytotoxic behavior, were selected for further in vivo evaluation.

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Purpose: ZD6126 is a novel vascular targeting agent currently undergoing clinical evaluation. It acts by destabilizing the microtubulin of fragile and proliferating neoendothelial cells in tumors. The drug leads to blood vessel congestion, the selective destruction of the vasculature, and extensive necrosis in experimental tumors. The aim of the study reported here was to assess the ability of dynamic contrast enhanced magnetic resonance imaging (MRI) to measure the antivascular effects of ZD6126 in tumors.Experimental Design: The work was carried out in mice bearing C38 colon adenocarcinoma and in patients with advanced cancers. MRI was performed before and 6 h (human tumors) or 24 h (C38 tumors) after i.v. drug administration. Contrast agent (gadolinium diethylenetriaminepentaacetate) enhancement was characterized by the initial area under the gadolinium diethylenetriaminepentaacetate uptake versus time curve (IAUC). IAUC reflects blood flow, vascular permeability, and the fraction of interstitial space.Results: The median IAUC was reduced in all C38 tumors after ZD6126 administration [by 6 -48% at 50 mg/kg (n ‫؍‬ 3)], 58 -91% at 100 mg/kg (n ‫؍‬ 4), and 11-93% at 200 mg/kg (n ‫؍‬ 6). In contrast, the administration of vehicle only led to no consistent change in median IAUC (n ‫؍‬ 4). The ZD6126-induced changes in median IAUC appeared to be dose dependent (P ‫؍‬ 0.045). No ZD6126-induced changes were apparent in murine muscle. Similar effects were seen in preliminary data from human tumors (11 tumors studied, 9 patients). At doses of 80 mg/m 2 and higher, the median IAUC post-ZD6126 treatment was reduced in all of the tumors studied (8 tumors, 6 patients) to 36 -72% from the baseline value. There was a significant trend of increasing reductions with increasing exposure (P < 0.01). No drug-induced changes in human muscle or spleen IAUC were apparent. The reproducibility of the median IAUC parameter was investigated in patients. In 19 human tumors (measured in 19 patients) inter-and intratumor coefficients of variation were 64 and 18%.Conclusions: The contrast enhanced-MRI measured median IAUC is a useful end point for quantifying ZD6126 antivascular effects in human tumors.