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Experimental Therapeutics |
Endocrine, Polypeptide and Cancer Institute, Veterans Administration Medical Center, New Orleans, Louisiana 70112-1262 [A. P., A. V. S., A. N., H. K., F. H., G. H.], and Section of Experimental Medicine, Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana 70112-2699 [A. P., A. V. S., A. N., H. K., G. H.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSEvaluation of ToxicityStatistical AnalysisRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSEvaluation of ToxicityStatistical AnalysisRESULTSDISCUSSIONREFERENCES |
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30,000 new cases of RCC and 12,000 deaths from this malignancy were
estimated for 1999 (2)
. Approximately one-third of the RCC
cases have documented metastatic spread at the time of the initial
presentation, and 50% of patients with presumably organ-confined
disease who are treated with radical nephrectomy are expected to
develop metastases within 10 years (3)
. The prognosis for
metastatic RCC remains dismal because of its resistance to both
chemotherapy and radiotherapy (4)
. Immunotherapy of
advanced RCC has only a marginal effectiveness, whereas its side
effects substantially decrease the quality of life (5, 6, 7)
. To overcome the problem of chemoresistance, efforts have been made to use cytotoxic drugs in combination with agents that can reverse the MDR mechanism (8) . This approach, however, has led only to an increased toxicity to normal organs that are protected by MDR, such as bone marrow or brain (9) . Alternatively, the MDR in cancer cells can be abolished by enhanced local accumulation of a cytotoxic agent. This can be achieved by targeted delivery of cytotoxic radicals coupled to carriers such as monoclonal antibodies or analogues of peptide hormones that preferentially bind to malignant cells (10 , 11) . Thus, cytotoxic hybrids of peptide hormones such as LHRH, bombesin, or SST that can be targeted to their respective receptors on various tumors were shown to be more potent and less toxic than their unconjugated cytotoxic radicals (11) . One of these cytotoxic analogues, AN-238, consisting of 2-pyrrolinodoxorubicin (AN-201) linked to carrier SST analogue RC-121, was recently demonstrated to strongly inhibit experimental SST receptor-positive tumors that are resistant to conventional chemotherapeutics (12 , 13) .
Several previous reports demonstrated that most kidney neoplasms express receptors for SST (14, 15, 16) . Thus, 72% of specimens of human RCC were shown to bind the SST octapeptide analogue 125I-[Tyr3]-octreotide with high affinity (14) . PCR analysis of another series of 13 samples of human RCC revealed that subtype 2 of the SST receptor (sst2) was expressed in all of the specimens, whereas sst1 and sst4 were expressed in 85 and 46% of the specimens, respectively (15) . In a clinical setting, the scintigraphy with radiolabeled octreotide was useful for the visualization of RCC in patients, especially in cases with multiple lesions (16) . These findings suggest that targeted chemotherapy with cytotoxic SST analogues may have potential application in SST receptor-positive RCC.
In the present study, we investigated the effectiveness of SST receptor-targeted chemotherapy in experimental models of human RCC. We first showed that cytotoxic SST analogue AN-238 binds selectively to SST receptor-positive RCC lines and inhibits their proliferation in vitro. We then demonstrated that analogue AN-238 inhibits the growth and metastatic dissemination of RCC in vivo. These findings, which suggest that targeted chemotherapy based on AN-238 could be considered for patients with advanced, SST receptor-positive RCC, are described herein.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSEvaluation of ToxicityStatistical AnalysisRESULTSDISCUSSIONREFERENCES |
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Cell Lines and Animals
SW-839, 786-0, and CAKI-1 human RCC cell lines were obtained
from the American Type Culture Collection (Manassas, VA) and maintained
in culture as described previously (20)
. Male athymic (Ncr
nu/nu) nude mice, 6 weeks old on arrival, were obtained
from the National Cancer Institute (Frederick Cancer Research and
Development Center, Frederick, MD) and housed in laminar airflow
cabinets under pathogen-free conditions with a 12-h light/12-h dark
schedule and fed autoclaved standard chow and water ad
libitum. All experiments were performed in accordance with
institutional guidelines for animal care.
RNA Isolation and RT-PCR
The expression of sst2A,
sst5, and glyceraldehyde 3-phosphate
dehydrogenase (internal control) in RCCs was examined by RT-PCR
as described previously (12)
, using gene-specific primers
for hsst2A (sense, 5'-ATGGACATGGCGGATGAGCCACT-3';
antisense, 5'-TACTGGTTTGGAGGTCTCCATTGA-3'), hsst5
(sense, 5'-CGTCTTCATCATCTACACGG-3'; antisense,
5'-GGCCAGGTTGACGATGTTGA-3'). PCR products were separated
electrophoretically on 8% polyacrylamide gels and stained with silver.
Receptor Binding Assay
Binding of octapeptide RC-160 to SST receptors on tumor membrane
preparations was determined by ligand competition assays using
125I-labeled RC-160, as reported previously
(13)
. Binding of the cytotoxic SST analogue AN-238 to
tumor membranes was measured in displacement experiments based on
competitive inhibition of 125I-RC-160 binding
using various concentrations of AN-238
(10-6–10-12
M). The IC50 was calculated by a
computerized curve-fitting program, and is defined as the concentration
causing a 50% inhibition of 125I-RC-160 binding
(13)
.
In Vitro Targeting and Microsatellite Analysis
In vitro targeting to SST receptor-positive RCC was
demonstrated using microsatellite analysis as described in detail
previously (21)
. The method is based on the assumption
that the intensity of cell line-specific alleles containing the D3S2418
microsatellite marker is proportional to the number of viable cells.
Briefly, cocultured 786-0 cells (105) expressing
sst5, and SST receptor-negative CAKI-1 cells
(4x105) were exposed to 10
nM AN-201 or 10 nM AN-238
for 30 min and 1 h. Untreated cells were used as controls. After
the treatment, the cells were washed twice with PBS and cultured for an
additional 7 days (cells exposed to AN-201) or 4 days (cells treated
with AN-238) in fresh medium that did not contain cytotoxic agents.
Genomic DNA was extracted by the standard phenol-chloroform method.
Microsatellite marker D3S2418 was obtained from Research Genetics
(Huntsville, AL). Fifty ng of DNA were amplified as described
previously (21)
. Five µl of each PCR product were
electrophoresed in a 10% polyacrylamide gel, stained with silver, and
semi-quantified using a scanning densitometer (Model GS-700; Bio-Rad,
CA). The ratio of CAKI-1/786-0-specific bands for microsatellite marker
D3S2418 was calculated to identify the cell line that was affected
preferentially by the treatment.
Experimental Protocols
s.c. Implantation.
All tumors were transplanted s.c. as described previously
(20)
. Experiments 1 (SW-839 RCC line) and 2 (786-0 RCC
line) were started when tumors had grown to a volume of 60–70
mm3. In each experiment, three groups of seven to
eight mice received three i.v. injections of AN-201 at 150 nmol/kg,
AN-238 at 150 nmol/kg, or vehicle only (controls), administered on days
1, 8, and 21. Cytotoxic compounds were dissolved in 20 µl of 0.1 N
acetic acid and diluted with 6% (w/v) aqueous D-mannitol
(Sigma Chemical Co., St. Louis, MO) solution. Tumor volume
(length x width x height x 0.5236) and BW were measured weekly. The experiments were
terminated 2 weeks after the third injection. Experiment 3 (CAKI-1 RCC
line) was started when tumors measured 30 mm3.
Three groups of mice received i.v. injections of AN-201 at 150 nmol/kg
(n = 8), AN-238 at 150 nmol/kg
(n = 9), or vehicle only (controls,
n = 8) on day 1, followed by a second
administration on day 8. BW and tumor volume were recorded weekly, and
the experiment was terminated after 4 weeks. Tumor specimens were
snap-frozen and stored at -70°C for the receptor binding assay and
extraction of RNA for RT-PCR.
Orthotopic Implantation (Experiment 4).
For the evaluation of SST receptor-targeted chemotherapy in a model of
disseminated RCC, mice were implanted orthotopically with 786-0 tumors.
Tumor tissue, harvested aseptically from donor animals after 8 weeks of
s.c. growth, was cleaned of connective tissue and necrotic parts,
weighed, mechanically minced in RPMI 1640, and pushed through a
medium-mesh tissue sieve. The tissue suspension was centrifuged for 10
min at 1000 rpm; the supernatants were then removed, and the pellets
were resuspended in RPMI 1640 at a final concentration of 500 mg tumor
tissue/ml. Mice received injections of 0.02 ml of the suspension
(corresponding to 10 mg of tumor tissue) under the capsule of the left
kidney. Two weeks later, animals were randomly divided into three
groups for treatment with AN-238 (n = 7),
AN-201 (n = 6), or vehicle solution
(n = 6). The compounds were administered
three times at a dose of 150 nmol/kg BW at intervals of 2 weeks. Mice
were killed 14 days after the last injection (8 weeks after
implantation) or when they became moribund. At the autopsy, tumor
weight was calculated by subtracting the weight of the right (normal)
kidney from the weight of the left kidney (implanted with tumor). Mice
were carefully checked under a dissecting microscope for the presence
of gross metastases in lymph nodes, lungs, and other organs.
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Evaluation of Toxicity |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSEvaluation of ToxicityStatistical AnalysisRESULTSDISCUSSIONREFERENCES |
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Statistical Analysis |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSEvaluation of ToxicityStatistical AnalysisRESULTSDISCUSSIONREFERENCES |
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSEvaluation of ToxicityStatistical AnalysisRESULTSDISCUSSIONREFERENCES |
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). We found that SW-839 expressed mRNA for sst2A
but not for sst5. In contrast, mRNA for
sst5 but not for sst2A
could be detected in 786-0 tumors. High-affinity binding sites for
125I-labeled RC-160 were found in tumor membrane
preparations of both lines (Table 1)
. Cytotoxic SST analogue AN-238
also exhibited high-affinity binding to membranes of both lines, as
expressed by IC50 values of 7.38 ± 0.68 nM for SW-839 and 2.04 ± 0.25
nM for 786-0 (Table 1)
. CAKI-1 renal cancers did not
express mRNA for sst2A and
sst5. No binding of radiolabeled RC-160 was
detected on cell membranes of CAKI-1 tumors.
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A presents the intensity of D3S2418 microsatellite alleles
in cocultured sst5-positive 786-0 cells and SST
receptor-negative CAKI-1 cells. Compared with untreated coculture,
exposure to 10 nM AN-238 increased the ratio of
CAKI-1/786-0-specific bands from 0.3:0.7 to 0.67:0.33 after 30 min and
to 0.57:0.43 after 1 h (Fig. 1B
). In contrast, the
radical AN-201 at equimolar concentrations did not preferentially
affect either of the two lines, as shown by the CAKI-1/786-0 ratio of
0.18:0.82 after 30 min and 0.2:0.8 after 1 h of incubation.
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presents the effect of cytotoxic SST analogue AN-238 and its radical
AN-201 on the growth of three human RCC xenografts in murine hosts. In
sst2A-positive SW-839 tumors and in the 786-0
line expressing sst5, the treatment was started
when tumors had reached 60–70 mm3 and consisted
of three i.v. injections of 150 nmol/kg of AN-201 or AN-238 on days 1,
8, and 21 (Fig. 2, A and B
). In both models, the
inhibition of tumor progression was already visible after two
injections of AN-238. This inhibitory effect was further reinforced
after the third injection. At the end of the experiments, the volume of
SW-839 tumors was decreased by 67.2% (P < 0.05 versus control), whereas the average size of the 786-0
RCC was reduced by 78.3% (P < 0.01
versus control). Treatment with AN-238 significantly
prolonged the tumor doubling time from 13 ± 2.2 to
22.2 ± 3.2 days (P < 0.05)
in the SW-839 model, and from 10 ± 1.0 to
31.1 ± 7.1 days (P < 0.05)
in 786-0 tumors, as compared with controls. In both experiments, the
unconjugated cytotoxic radical AN-201 had no significant effect on
tumor growth, the reduction in tumor volume being only 27% in SW-839
line and 40% in 786-0 RCC line (Fig. 2, A and B
).
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30 mm3 in size. Two
injections of 150 nmol/kg of AN-238 exerted only a minor inhibition of
tumor growth, which was comparable to the effect of AN-201 (Fig. 2C
). Thus, there was a 32% reduction in final tumor volume
in AN-238-treated animals and a 23% decrease in mice given AN-201,
compared with the controls.
Inhibition of Orthotopic Growth and Development of Metastases of
786-0 RCC.
The treatment, consisting of three i.v. injections of AN-238 or AN-201
at 150 nmol/kg, was given to nude mice at biweekly intervals starting 2
weeks after orthotopic implantation of 786-0 RCC. Six weeks after the
initiation of treatment, three of seven mice receiving AN-238 were
found to be tumor free, whereas in three other animals, the tumor mass
was <30 mg (Table 2
). One tumor in this group was disproportionately large (320 mg) and did
not express SST receptors, as demonstrated later by a radioligand
binding assay. The mean weight of AN-238-treated tumors was
55.3 ± 44.3 mg, corresponding to an 87% reduction
(P < 0.001) compared with control tumors,
which measured 414.2 ± 41.0 mg (Fig. 3, A, B, and C)
. The weight of tumors in
the group treated with AN-238 was also significantly lower
(P < 0.05) than that in animals given AN-201
(270.2 ± 60.3 mg). The effect of AN-201 on the weight
of primary tumors (35% reduction) was not significant compared with
the control group. Five of six control animals (83%) and the same
number of AN-201-treated mice developed metastases into the regional
lymph nodes (hilar and retroperitoneal; Fig. 3D
) and distant
lymph nodes, whereas the incidence of lymphatic spread in mice given
AN-238 was only 14% (one of seven animals; Table 2
). The rate of lung
metastases found in control and AN-201 groups was 83 and 50%,
respectively. However, no lung metastases developed in any of the seven
mice treated with AN-238. Distant cancer spread to other organs was
detected in two animals each from both the control and AN-201-treated
groups (Table 2)
, but not in mice receiving AN-238.
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). The WBC count, as determined 2 weeks after the third injection, was
significantly decreased by 50% in the AN-201 group
(P < 0.05) and by 65% in animals given
AN-238 (P < 0.05), but both values were
within the normal range for nude mice. To estimate the side effects
caused by targeting to normal organs that express SST receptors, at the
end of the experiment we evaluated the effects of AN-201 and AN-238 on
the pituitary reserve of GH, using i.v. stimulation with GHRH. The
levels of GH evoked by GHRH in mice treated with AN-238 or AN-201 were
lowered nonsignificantly by 25 and 12%, respectively, compared with
the control (Table 3)
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSEvaluation of ToxicityStatistical AnalysisRESULTSDISCUSSIONREFERENCES |
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Two RCC lines used in the present study, SW-839 and 786-0, showed high-affinity binding sites for radiolabeled SST analogue RC-160, which is structurally similar to the carrier octapeptide RC-121 used in cytotoxic SST analogue AN-238. The receptor subtypes were identified as sst2A in SW-839 and sst5 in 786-0 cancers. In accordance with a previous report on the lack of binding of SST octapeptides to CAKI-1 RCC (20) , we were not able to detect the expression of sst2A or sst5 in this cell line. This allowed us to use it as a negative control for testing the specificity of SST receptor targeting in vitro and in vivo. Thus, the proportion of SST receptor-positive RCC lines chosen for this study (two of three) corresponds roughly to the incidence of 125I-[Tyr3]octreotide-preferring binding sites (72%) demonstrated on the specimens of human RCC (14) . Among SST receptor subtypes detected on surgical specimens of RCC, sst2 appears to be the most common, whereas sst1 and sst4 occur less frequently (15) . However, no data are available on the incidence of sst5. The mRNA encoding for sst3, which displays a moderate binding of SST octapeptides (22) , was not detected in RCC specimens (15) . In accordance with the results for RC-160, obtained by radioligand binding assays and the pattern of expression of SST receptor subtypes, we showed high-affinity binding of AN-238 to membranes of SW-839 and 786-0 tumors.
Using the analysis of alleles for the D3S2418 microsatellite marker in cocultured 786-0 and CAKI-1 lines, we demonstrated the selective cytotoxicity of AN-238 against cells expressing SST receptors. Cytotoxic SST analogue AN-238 preferentially decreased the number of sst5-positive 786-0 cells. In contrast, an equimolar amount of the radical AN-201 did not affect preferentially any of the two lines. This finding supports the hypothesis that accumulation of a cytotoxic drug mediated by SST receptors can overcome the chemoresistance in neoplastic cells.
A comprehensive series of in vivo experiments was conducted to evaluate the efficacy and specificity of SST receptor-targeted chemotherapy in human RCC. A significant inhibition of tumor growth after treatment with cytotoxic SST analogue AN-238 was observed in the sst2A-positive SW-839 line and in 786-0 tumors that express sst5. In both models, equimolar doses of unconjugated cytotoxic radical AN-201 exerted only a nonsignificant effect. In accord with the lack of binding of octapeptide SST analogues to CAKI-1 RCC in vitro, the effect of AN-238 on the growth of CAKI-1 tumors was marginal and comparable to the inhibition caused by the radical AN-201. These results indicate that the tumor inhibition achieved by AN-238 depends on the specific binding of the cytotoxic conjugate by SST receptor-positive tumors and that both sst2 and sst5 are essentially equally effective in mediating the antitumoral effect of AN-238. This also implies that chemotherapy targeted to SST receptors may be effective in cancers that express predominantly sst5, such as colon or primary prostate carcinomas (23 , 24) .
In experiment 4, we evaluated the efficacy of SST analogue AN-238 in a model of disseminated RCC. Six weeks after initiation of the treatment, the mean weight of 786-0 primary tumors treated with AN-238 was reduced by 87% compared with controls. In three of seven mice, the tumors appeared to be eradicated, and only residual connective tissue was found at the implantation site. In one mouse, however, no response was observed, which was later explained by the lack of SST binding sites on this particular tumor, as determined by a radioligand assay. Loss of SST receptors after several passages of experimental tumors was observed previously (25) and is a result of the clonal growth and heterogeneity of neoplastic tissue. A slightly stronger effect of AN-238 on the growth of orthotopic tumors compared with its action on s.c. xenografts was noted in an earlier study (12) , and is most likely caused by better vascularization and hence a higher drug supply to the neoplastic tissue. The targeting of AN-238 to tumor vasculature expressing sst2 may also account for a better response of orthotopic tumors (26) . The cytotoxic radical AN-201 affected the progression of orthotopic 786-0 tumors only nonsignificantly. Another promising observation is that the treatment with AN-238 almost completely eliminated the lymphatic and hematogenous spread of 786-0 cancers. A potent inhibition of tumor dissemination by cytotoxic SST analogue AN-238 was similarly observed in orthotopic PC-3 human prostate cancers expressing sst2A and sst5 (12) . The mechanisms of inhibition of metastatic lesions may include the growth arrest of primary tumors, thus preventing the dissemination of the cancer and/or targeting to already established micrometastases, leading to their regression. Because metastases of human RCC express SST receptors as demonstrated by scintigraphy with radiolabeled octreotide (16) , it could be expected that targeted chemotherapy with AN-238 may significantly improve the management of disseminated RCCs.
In the present study, we observed similar side effects of AN-238
and AN-201 administered at the cumulative dose of 450 nmol/kg. Because
AN-201 is linked to the carrier peptide through an ester bond,
comparable toxicity patterns of both cytotoxic compounds in mice
suggest a rapid deconjugation of the radical from the conjugate by
serum CE (EC 3.1.1.1). CE activity in mouse serum is 10-fold higher
than in human serum (27)
. Thus, in a recent study we
investigated the tolerance to AN-238 and AN-201 in tumor-free nude mice
with CE activity suppressed by diisopropyl fluorophosphate
(28)
. We found that the tolerance to AN-238 could be
doubled, whereas the tolerance to AN-201 was not affected
(28)
. Under these conditions, the half-life in mouse serum
of cytotoxic LHRH analogue AN-152, consisting of
doxorubicin-14-O-hemiglutarate linked to
[D-Lys6]LHRH, was
extended from 20 to 70 min, which is still much shorter than the 120
min observed in human serum. Because the tolerance to AN-238 depends on
its stability in serum, it could be expected that AN-238 will be even
less toxic in human beings than in nude mice.
The study of the tolerance of AN-238 in tumor-free nude mice after pharmacological inhibition of CE activity also suggests that the lower general toxicity of AN-238 is the result of drug disposition to normal tissues expressing SST receptors (28) . This is in accordance with the in vivo uptake of radioactivity by SST receptor-positive organs after administration of radiolabeled SST analogues (29, 30, 31) . To evaluate the possible side effects of targeting SST receptors in normal tissues, we investigated in the present study the function of the pituitary gland in animals treated with a cumulative dose of 450 nmol/kg of AN-238 or AN-201. Both compounds diminished nonsignificantly the GH response to GHRH compared with the controls, but the pituitary reserve of GH in mice given AN-238 was lower than in animals given AN-201. Likewise, a selective impairment of the pituitary function was observed in rats after administration of the cytotoxic LHRH analogue AN-207, which contains AN-201 (32) . However, the pituitary insufficiency caused by AN-207 is only transient, and recovery occurs in 3 weeks. Similarly, a good tolerance to AN-238 at cumulative doses of 800–900 nmol/kg by nude mice with suppressed CE activity suggests that the side effects of SST receptor-targeted chemotherapy are much less harmful than the general adverse reactions to unconjugated cytotoxic radicals, such as myelosuppression (28) . This view is also supported by preliminary clinical studies that showed no or only low-grade toxicity to the pituitary, the kidneys, and the bone marrow after administration of radiolabeled SST analogues to cancer patients, whereas a significant reduction in tumor progression was achieved (31 , 33 , 34) .
In conclusion, we demonstrate here that the cytotoxic SST analogue AN-238 strongly inhibits the growth of human RCCs expressing SST receptors. Because chemotherapy with AN-238 can be also targeted to SST receptor-positive RCC metastases, this therapeutic modality might be of benefit to patients with residual cancer tissue after radical nephrectomy or with metastatic disease.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 This work was supported by The Medical Research
Service of the Veterans Affairs Department and a grant from ASTA Medica
AG, Frankfurt am Main, Germany to Tulane University School of Medicine
(both to A. V. S.). 
2 On leave from Department of Neuroendocrinology,
Medical Center of Postgraduate Education, Warsaw, Poland 04-158.
3 To whom requests for reprints should be
addressed, at Veterans Administration Medical Center, 1601 Perdido
Street, New Orleans, LA 70112-1262. Phone: (504) 589-5230; Fax:
(504) 566-1625.
4 The abbreviations used are: RCC, renal cell
carcinoma; MDR, multidrug resistance; LHRH, luteinizing
hormone-releasing hormone; SST, somatostatin; GHRH, growth
hormone-releasing hormone; RT-PCR, reverse transcription-PCR; BW, body
weight; GH, growth hormone; CE, carboxylesterase.
Received 12/ 6/99. Accepted 4/ 3/00.
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REFERENCES |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSEvaluation of ToxicityStatistical AnalysisRESULTSDISCUSSIONREFERENCES |
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-1b compared with placebo in metastatic renal-cell carcinoma. N. Engl. J. Med., 338: 1265-1271, 1998.
-2a, or both in metastatic renal-cell carcinoma. N. Engl. J. Med., 338: 1272-1278, 1998.This article has been cited by other articles:
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K. Szepeshazi, A. V. Schally, G. Halmos, P. Armatis, F. Hebert, B. Sun, A. Feil, H. Kiaris, and A. Nagy Targeted Cytotoxic Somatostatin Analogue AN-238 Inhibits Somatostatin Receptor-positive Experimental Colon Cancers Independently of Their p53 Status Cancer Res., February 1, 2002; 62(3): 781 - 788. [Abstract] [Full Text] [PDF]
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 G. Halmos, A. V. Schally, J. L. Varga, A. Plonowski, Z. Rekasi, and T. Czompoly Human renal cell carcinoma expresses distinct binding sites for growth hormone-releasing hormone PNAS, September 12, 2000; 97(19): 10555 - 10560. [Abstract] [Full Text] [PDF]
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), or vehicle solution (control; 
). The
treatment was started when tumor volume had reached 60–70
mm3 and was administered on days 1, 8, and 21. In the
experiment with the SST receptor-negative CAKI-1 line
(C), two injections of 150 nmol/kg of AN-201, AN-238, or
placebo were given 7 days apart when the initial tumor volume was 30
mm3. Arrows indicate the days of injection;
bars, SE; *, P < 0.05
versus control; **, P < 0.01 versus control.