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Clinical Cancer Research Vol. 7, 1867-1872, July 2001
© 2001 American Association for Cancer Research

Advances in Brief

Protein Binding Alters the Activity of Suramin, Carboxyamidotriazole, and UCN-01 in an ex Vivo Rat Aortic Ring Angiogenesis Assay1

Erwin A. Krüger and William D. Figg2

Medicine Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892


   ABSTRACT
Top
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 
Angiogenesis inhibitors are currently in clinical development for cancer. These agents pose unique developmental challenges: (a) determining maximum biological doses versus maximum tolerated doses; (b) defining response criteria other than objective tumor responses; and (c) defining safe regimens for prolonged, chronic administration. The current in vitro angiogenesis assays used in the screening and preclinical development of antiangiogenic agents each have their own advantages and disadvantages, yet all seem to underestimate the importance and impact of in vivo protein-drug interactions. We have developed a human serum rat aortic ring angiogenesis bioassay that highlights protein binding concerns using three anticancer agents that have documented antiangiogenic activity: suramin, carboxyamidotriazole, and 7-hydroxystaurosporine. We have determined that the bioassay concentrations of suramin (100 µg/ml) and 7-hydroxystaurosporine (>1 µg/ml), but not carboxyamidotriazole (>=60 µg/ml), that inhibit microvessel formation are consistent with target plasma levels achievable in the clinic. We conclude that assays such as the human serum rat aortic ring bioassay may prove useful in predicting the concentrations of protein-bound antiangiogenic agents required for free fraction biological activity.


   Introduction
Top
 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 REFERENCES
 
The discovery that angiogenesis is critical for the growth and metastasis of solid tumors has been established (1 , 2) . Sufficient evidence supporting angiogenesis as a therapeutic target for cancer has justified the clinical development of antiangiogenic compounds. However, because angiogenesis inhibitors are speculated to be essentially cytostatic, the traditional objective response criteria for developing cytotoxic agents may be inappropriate, and new assays for detecting the maximum biological response of these agents are needed. In effect, standardized bioassays are required to detect doses with maximal biological activity, which may be significantly lower than the maximum tolerated dose. It is also important to realize that these agents will require innovative correlative assays to validate and monitor their pharmacokinetics and pharmacology. In particular, the effects of protein binding must be investigated, because these effects can be underestimated by current in vitro angiogenesis assays. These oversights are not limited to angiogenesis assays, because most preclinical in vitro assays for traditional anticancer agents are conducted with low (10%) FBS concentrations. It is assumed the free fraction of these drugs can exhibit their biological effects, whereas sequestered drug fractions are inactive. Several antiangiogenic compounds, with promising preclinical activity, have demonstrated unexpected clinical pharmacology, pharmacokinetics, and toxicity profiles, which may involve or be explained by protein binding effects. Among them are suramin, CAI,3 and UCN-01 (Fig. 1)Citation .



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  		Fig. 1. The chemical structures for suramin, CAI, and UCN-01.

 
Suramin is a polysulfonated naphthylurea evaluated as an antineoplastic and antiangiogenic agent for several solid tumors, in particular, prostate carcinoma (3, 4, 5, 6, 7, 8) . The biological action of suramin is varied: (a) it inhibits binding of platelet-derived growth factor, FGF-1, FGF-2, and vascular endothelial growth factor; (b) it interferes with glycosaminoglycan catabolism; (c) it disrupts intracellular signal transduction or DNA replication; and (d) it inhibits in vitro and in vivo angiogenesis in the rat aortic ring assay, Matrigel sponge assay, and the chick chorioallantoic membrane assay (9, 10, 11, 12, 13, 14) . Clinically, suramin has met limited success because of drug-limiting toxicity (particularly polyneuropathy), complex pharmacokinetics, the need for hydrocortisone coadministration to reduce adrenal toxicity, and a relatively narrow therapeutic window (100–300 µg/ml; 8 , 15, 16, 17 ).

CAI is a synthetic inhibitor of nonexcitable calcium channels that has antiangiogenic, antiproliferative, and antimetastatic activity in vitro and in vivo (18, 19, 20, 21, 22) . Clinically, CAI has been studied in Phase I clinical trials in patients with refractory tumors and one Phase II trial in androgen-independent prostate cancer (23, 24, 25) . Peak plasma concentrations ranged from 0.4–5.1 µg/ml with the main dose-limiting toxicity being peripheral neuropathy or vision disturbances (23, 24, 25) . CAI demonstrated disease stabilization in renal, pancreatic, melanoma, ovarian, and non-small cell lung cancers but no clinical activity in androgen-independent prostate cancer (16, 17, 18, 19, 20, 21, 22, 23, 24, 25) . Phase II studies are still ongoing in ovarian and renal cell carcinoma.

UCN-01 is a selective inhibitor of protein kinase C that inhibits the growth of human and murine solid tumor cells in vitro and in vivo, synergizes with standard anticancer agents in vivo and in vitro, and at low concentrations inhibits endothelial cell proliferation (26, 27, 28) . UCN-01 has demonstrated unexpected pharmacokinetics in the clinic and in preclinical models caused by high affinity protein binding and slow dissociation from human {alpha}1-acid glycoprotein (29, 30, 31) . The highest achievable serum concentrations of UCN-01 thus far approximates 28.1 µg/ml (58.2 µM) (32) .

We have modified the culture conditions (from EBM-2 media to 100% human serum) of the rat aortic ring assay to highlight the importance of protein binding effects on the activity of suramin, CAI, and UCN-01. We report that these compounds, strongly bound to serum proteins, require concentrations that do not always correlate with clinically achievable doses to detect an antiangiogenic effect in vitro. These protein-drug interactions may be responsible for their limited clinical activity. Suramin, CAI, and UCN-01 have a clinical history, have shown antiangiogenic activity preclinically, and are prototypical compounds which demonstrate the need to design in vitro angiogenesis bioassays that better represent in vivo protein-drug interactions.


   Materials and Methods
Top
 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 REFERENCES
 
Reagents.
Growth factor-free EBM-2 was obtained from Clonetics Corp. (San Diego, CA). EGM-2 is composed of EBM-2 with the addition of a SingleQuot Bullet Kit, also provided by Clonetics Corp., to include 2% FBS and a variety of endothelial cell-specific growth factors. CAI (NSC 609974), suramin (NSC 34936), and UCN-01 (NSC 638850) were provided by the Developmental Therapeutics Program, National Cancer Institute (Rockville, MD). Juvenile male Sprague Dawley rats were purchased from Charles River Breeding Laboratories. Commercial human serum was purchased from Gemini Bioproducts (Woodland, CA). Donor human serum was prepared by collecting whole blood in red top serum separator tubes, allowed to clot for 15 min, and centrifuged at 2500 rpm for 5 min. Serum was aliquoted and either used fresh or frozen at -70°C. Stored material was used within 2 weeks of collection.

Rat Aortic Ring Bioassay.
Twelve-well tissue culture grade plates were covered with 250 µl of Matrigel (Becton Dickinson, Bedford, MA) and allowed to gel for 45 min at 37°C, 5% CO2. Thoracic aortas were excised from 8- to 10-week-old male Sprague Dawley rats (range, 292–307 g), and the fibroadipose tissue was removed. The aortas were sectioned into 1-mm-long cross-sections, rinsed eight times with EGM-2 (Clonetics Corp.), placed on the Matrigel-coated wells, covered with an additional 250-µl Matrigel, and allowed to gel for 45 min at 37°C, 5% CO2. The rings were cultured for 24 h in 1 ml of EGM-2. After the 24 h incubation, the medium was removed and replaced with 1-ml commercial or human serum. Suramin, CAI, and UCN-01 were dissolved in DMSO and diluted into human serum cultures (v/v < 0.5%). Aortic rings were photographed on day 5. All assays were performed in duplicate.

Image Analysis.
The area of angiogenic sprouting was calculated using the NIH Image v1.62 f software program (NIH, Bethesda, MD). Microvessel densities are reported in square pixels.


   Results
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 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 REFERENCES
 
To determine whether human serum would stimulate microvessel formation, serum was collected from a single donor and used as a control. Pooled serum and single donor serum from a commercial source (Gemini Bioproducts) were used for comparison. The results showed both fresh single donor and commercial single donor serum-stimulated microvessel formation, whereas pooled serum failed to promote angiogenesis (Fig. 2)Citation . Commercial single donor serum was less potent at stimulating angiogenesis. We concluded that fresh single donor serum would yield optimal outgrowth, and fresh single donor serum was chosen for all subsequent protein binding bioassays.



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  		Fig. 2. Angiogenic stimulation of volunteer single donor serum versus commercial serum. A, microvessel outgrowth of 100% fresh human serum; B, microvessel outgrowth of 100% single donor commercial serum; C, microvessel outgrowth of 100% pooled commercial serum. Photographs are representative rings from duplicate assays.

 
The dose response of suramin, CAI, and UCN-01 experiments were analyzed. Suramin stock solutions were prepared in DMSO and diluted into human serum (v/v < 0.5%) at concentrations yielding concentrations of 100 µg/ml and 50 µg/ml. Suramin showed complete inhibition at 100 µg/ml and failed to show antiangiogenic activity at 50 µg/ml (Fig. 3)Citation .



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  		Fig. 3. Suramin dose-response activity profile in the rat aorta bioassay. A, suramin at 50 µg/ml in growth factor-free EBM-2; B, suramin at 50 µg/ml in 100% human serum; C, suramin at 100 µg/ml in 100% human serum. Photographs are representative rings from duplicate assays.

 
CAI stock solutions were prepared in DMSO and diluted into human serum (v/v < 0.5%) at concentrations yielding 240 µg/ml, 60 µg/ml, 12 µg/ml, and 4 µg/ml. Microvessel outgrowths were inhibited in a dose-dependent manner: 240 µg/ml showed complete inhibition, 60 µg/ml showed ~90% inhibition, and 12 and 4 µg/ml showed no inhibitory activity (Fig. 4)Citation . In short, high affinity protein binding of CAI at concentrations as high as 12 µg/ml was observed.



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  		Fig. 4. CAI dose-response activity profile in the rat aorta bioassay. Left panel: A, control microvessel outgrowth of human serum; B, CAI at 12 µg/ml in growth factor-free EBM-2; C, CAI at 240 µg/ml in human serum; D, CAI at 60 µg/ml in human serum; E, CAI at 12 µg/ml in human serum; F, CAI at 4 µg/ml in human serum. Photographs are representative rings from duplicate assays. Right panel: image analysis quantitation of CAI dose-response activity. Bars represent mean pixel density areas (pixels2) ± SD.

 
UCN-01 stock solutions were prepared in DMSO and diluted into human serum (v/v < 0.5%) at concentrations ranging between 1 and 250 µg/ml. No inhibitory activity was shown at 1 µg/ml, whereas complete inhibition was observed at all tested concentrations >1 µg/ml: 10, 20, 50, 100, 150, 200, and 250 µg/ml (Fig. 5)Citation .



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  		Fig. 5. UCN-01 dose-response activity profile in the rat aorta bioassay. A, control microvessel outgrowth of human serum; B, UCN-01 at 200 µg/ml in human serum; C, UCN-01 at 100 µg/ml in human serum; D, UCN-01 at 50 µg/ml in human serum; E, UCN-01 at 10 µg/ml in human serum; F, UCN-01 at 1 µg/ml in human serum.

 

   Discussion
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
REFERENCES
 
Angiogenesis is a critical process necessary for the growth and metastasis of tumors. Angiogenesis inhibitors are currently being evaluated in clinical trials worldwide as potential anticancer agents. However, angiogenesis inhibitors pose several developmental challenges. The hypothesis that antiangiogenic therapy will need to be prolonged for maximum benefit requires the ideal agents to be bioavailable, easily manufactured, and relatively free of side effects. Furthermore, because antiangiogenesis is not a traditional cytotoxic modality, monitoring drug efficacy and choosing response criteria unique to drugs categorized as biologicals are highly important. From a pharmacokinetics perspective, these drugs will also need to be evaluated and monitored with their in vivo protein binding interactions in mind. In preclinical screening assays, culture conditions in endothelial cell proliferation assays, tube formation assays, migration assays, or even the ex vivo rat aortic ring angiogenesis assay are either serum free or contain between 2 and 10% FBS. We concluded these standard in vitro angiogenesis assays may underestimate protein binding effects. Therefore, we investigated a modification of the rat aortic ring angiogenesis assay to account for serum protein-drug interactions, in effect providing a bioassay for antiangiogenic activity. We chose to evaluate the utility of this bioassay in predicting doses that are biologically active and comparing these doses to clinically achievable concentrations and therapeutic outcome.

Suramin has been limited in its clinical efficacy attributable in part by dose-limiting toxicities (15) . Suramin binds the angiogenic proteins platelet-derived growth factor, FGF-2, and vascular endothelial growth factor, which may contribute to its antiproliferative and antiangiogenic effects, and confirms its tendency to interact with serum proteins (9, 10, 11, 12) . We report that suramin does not demonstrate antiangiogenic activity in the rat aortic ring angiogenesis bioassay at 50 µg/ml but has significant activity at 100 µg/ml (Fig. 2)Citation . Clinically, the target plasma levels for suramin have between 50 and 300 µg/ml (7 , 8 , 33, 34, 35, 36) . Our data would have predicted biological activity with serum levels >=100 µg/ml, which is consistent with the clinical activity with this agent (7 , 8 , 33, 34, 35, 36) . However, because of its side effects, suramin can only be administered for short durations. Thus, the ideal continuous, prolonged drug exposure regimen is not practical. Nevertheless, the correlation between our in vitro activity and clinical data supports the usefulness of our bioassay in determining biologically active serum concentrations of suramin. Previous studies have investigated the utility of angiogenesis bioassays using endothelial cell migration assays and human serum samples from breast cancer patients receiving suramin, showing a correlation between high suramin concentrations and low angiogenic potential (7) . In short, our human serum rat aortic ring angiogenesis bioassay may also be a feasible tool for monitoring antiangiogenic activity in clinical settings.

CAI is known to be tightly protein bound (>99%) from preclinical and pharmacokinetic studies (18, 19, 20, 21 , 25) . Its clinical toxicities include reversible peripheral neuropathy and vision disturbances (21 , 25) . The clinical plasma concentrations of CAI have ranged from 0.4 to ~6.0 µg/ml, but concentrations between 2 and 4 µg/ml are targeted (18, 19, 20, 21, 22, 23, 24, 25) . We report that CAI demonstrates antiangiogenic activity well above the published clinically achievable doses, at 60 µg/ml, and complete inhibition at 240 µg/ml (Fig. 4)Citation . On the basis of our data, the bioassay would predict biological activity at a CAI concentration that is >=10-fold greater (60 µg/ml) than the highest published plasma concentration in humans. Furthermore, no activity was seen at 12 or 4 µg/ml, levels that have shown cytotoxicity and antiangiogenic effects in vitro. In short, our bioassay would suggest that CAI is too strongly protein bound to have the desired biological effects at doses being achieved in the clinic thus far. Results from ongoing clinical trials may answer some of these concerns.

UCN-01, a protein kinase C inhibitor, is in early clinical development. It has demonstrated unusual pharmacokinetics because of its high affinity for human {alpha}1-acid glycoprotein (29, 30, 31) . UCN-01 is currently in Phase I clinical trials in patients with refractory tumors. We report that our angiogenesis bioassay suggests UCN-01 to be biologically active at concentrations >1 µg/ml, particularly concentrations a magnitude higher (Fig. 5)Citation . It will be interesting to compare the drug concentrations achieved in Phase I trials, which have reached concentrations of 28.6 µg/ml (32) , with the predicted biologically active concentrations from our bioassay. To date, it is too early to draw conclusions about the UCN-01 concentrations showing antiangiogenic activity in our hands.

In summary, the clinical development of angiogenesis inhibitors will require innovative in vitro and in vivo assays and bioassays to screen and monitor their efficacy. In designing these assays, considering in vivo protein binding is important and largely underestimated by current angiogenesis assays. We suggest that bioassays, such as the human serum rat aortic ring assay described here, could be useful in predicting total drug concentrations with biological activity. Our study suggests that the clinically achievable concentrations of suramin and UCN-01, but not CAI, are close to or above those showing biological activity in a human serum rat aortic ring angiogenesis bioassay. Additional studies confirming the utility of angiogenesis bioassays are warranted.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 Supported in part by the National Center on Minority Health and Health Disparities, NIH, the Intramural Program of the National Cancer Institute, and the Angiogenesis Foundation, Inc. Back

2 To whom requests for reprints should be addressed, at National Cancer Institute, 10 Center Drive, Building 10, Room 5A-01, Bethesda, MD 20892. Phone: (301) 402-3622; Fax: (301) 402-8606; E-mail: wdfigg{at}helix.nih.gov Back

3 The abbreviations used are: CAI, carboxyamidotriazole; UCN-01, 7-hydroxystaurosporine; FGF, fibroblast growth factor; EBM, endothelial cell basal media; EGM, endothelial growth media; FBS, fetal bovine serum; NSC, National Service Center; v/v, volume for volume. Back

Received 10/ 2/00; revised 3/22/01; accepted 3/23/01.


   REFERENCES
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 

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Cancer Research Clinical Cancer Research
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