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Experimental Therapeutics |
Laboratory of Surgical Research [T. B., C. E. B., B. M. K., B. S., B. M., M. S. O., J. F.] and Division of Hematology/Oncology [T. B.], Children’s Hospital; Departments of Surgery and Cell Biology, Harvard Medical School [J. F.]; Department of Pediatric Oncology, Dana-Farber Cancer Institute [T. B.]; and the Joint Center for Radiation Therapy [M. S. O.], Boston, Massachusetts 02115
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDrug-resistant Tumor Growth...Eradication of Drug-sensitive...Eradication of Drug-resistant...DISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDrug-resistant Tumor Growth...Eradication of Drug-sensitive...Eradication of Drug-resistant...DISCUSSIONREFERENCES |
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Although tumor cells readily acquire resistance to cytotoxic chemotherapy, this would not be expected for vascular endothelial cells (5 , 6) . To more effectively suppress the proliferating endothelial cells in the tumor bed, a dosing schedule was developed that administered cyclophosphamide at shorter intervals without interruption. This antiangiogenic schedule of cyclophosphamide: (a) increased apoptosis of endothelial cells within the tumor bed; (b) secondarily increased apoptosis of cyclophosphamide-resistant tumor cells; (c) demonstrated long-term suppression of the growth of cyclophosphamide-resistant Lewis lung carcinoma and EMT-6/CTX breast carcinoma (7) , a significant improvement over the conventional schedule; (d) eradicated drug-sensitive Lewis lung carcinoma (8) and L1210 leukemia (9) tumors by avoiding acquired drug resistance, an outcome not possible with the conventional schedule; and (e) eradicated the majority of drug-resistant Lewis lung carcinomas when combined with another angiogenesis inhibitor, TNP-470 (10) .
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDrug-resistant Tumor Growth...Eradication of Drug-sensitive...Eradication of Drug-resistant...DISCUSSIONREFERENCES |
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In Vitro Experiments.
For proliferation, 12,500 bovine adrenal capillary endothelial cells
(12)
in DMEM and 10% bovine calf serum were plated onto
gelatinized (8)
24-well plates in quadruplicate. For
apoptosis and cell cycle determinations, 2 x 106 cells were similarly split into T150 flasks,
and 16 h later, the media were aspirated and replaced with DMEM
and 5% bovine calf serum with or without 5 ng/ml
bFGF3
(Scios Nova, Mountain View, CA) as indicated. Freshly reconstituted
4-hydroperoxycyclophosphamide (Omicron Biochemicals, San Antonio, TX),
which spontaneously converts to 4-HC in aqueous solution, was added at
the concentrations indicated, and 18 h later, the cells were
trypsinized and enumerated for proliferation as described previously
(8)
or washed with PBS and incubated with
annexin-fluorescein as per the ApoAlert Annexin V apoptosis detection
kit (Clontech, Palo Alto, CA). Cells were then washed in cold PBS,
fixed by drop-wise dispersion while vortexing into cold 80% ethanol,
and incubated for 30 min on ice. Cells were again washed in cold PBS.
Propidium iodide (Sigma, St. Louis, MO) and RNase A (Boehringer
Mannheim, Indianapolis, IN) were added to give a concentration of 2.5
and 50 µg/ml, respectively. Samples were incubated for 30 min at
37°C and analyzed by flow cytometry. For migration studies, bovine
capillary endothelial cells were exposed to 4-HC as described above.
Migration was performed as described previously (13)
without adding additional 4-HC.
Corneal Angiogenesis Assay.
The antiangiogenic efficacy of different schedules of cyclophosphamide
and other chemotherapeutic agents was screened using the 6-day mouse
corneal angiogenesis assay (8)
. Cyclophosphamide was
administered as described previously (6)
on schedules
detailed in "Results" and in Fig. 2, b and c
.
5-Fluorouracil (Roche Laboratories, Nutley, NJ) or 6-mercaptopurine
ribose phosphate (Sigma) was administered as daily bolus injections of
50 mg/kg/day x 5 days (conventional schedule) or as 50
mg/kg/day continuous infusions (antiangiogenic schedule) via Alzet
osmotic minipumps (#2001; ALZA Pharmaceuticals, Palo Alto, CA). Pumps
were surgically implanted in the peritoneal cavity of large (30–35-g)
C57Bl6/J mice on the day before corneal pellet implantation. Inhibition
was determined as described in the legend to Fig. 2
on day 6
(n = 4 mice/group; repeated twice with
similar results). Doxorubicin hydrochloride (Gensia Laboratories,
Irvine, CA) or the pegylated liposomal formulation (Doxil, Sequus
Pharmaceuticals, Menlo Park, CA) was administered in 5% dextrose in
water at 2.5 mg/kg (doxorubicin equivalent dose) once by tail vein
injection in severe combined immunodeficient (SCID) mice (Massachusetts
General Hospital, Boston, MA) 24 h after pellet implant.
Inhibition was similarly determined (n = 6
mice/group; experiment repeated twice with similar results).
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDrug-resistant Tumor Growth...Eradication of Drug-sensitive...Eradication of Drug-resistant...DISCUSSIONREFERENCES |
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Cyclophosphamide was then administered daily or every 3, 4, 5, 6, 7, or 8 days to mice bearing drug-resistant Lewis lung carcinoma. Each of our dosing schedules used higher doses and was more sustained than similar nonconventional schedules (15) reported previously for Lewis lung carcinoma (16 , 17) yet resulted in no more than 5% weight loss over the duration of the experiment. Cyclophosphamide (170 mg/kg) every 6 days proved more effective in controlling tumor growth than other cyclophosphamide schedules tested [including schedules with a higher dose intensity (e.g., 135 mg/kg every 4 days; data not shown)].
In Fig. 1a
, the growth of drug-resistant Lewis lung carcinoma in mice
treated with cyclophosphamide on a conventional schedule of the maximum
tolerated dose (Refs. 4
and 18
; 150 mg/kg
every other day for three doses given every 21 days = 450 mg/kg every 21 days) is compared to tumor growth on our
antiangiogenic schedule (170 mg/kg every 6 days). On the conventional
schedule, drug-resistant tumors escaped by day 13 and grew rapidly
(Fig. 1a
, inset). In addition, these mice lost 21% of body
weight, which was regained before the next treatment cycle. In
contrast, on the antiangiogenic schedule, there was no net tumor growth
for 36 days, and weight loss was less than 5%. After the first seven
cycles (36 days) of therapy on the antiangiogenic schedule, tumor
growth occurred at a slow rate. This partial escape from complete
suppression of a drug-resistant tumor may have resulted from the known
induction by cyclophosphamide of its own metabolism (19)
.
Similar results were obtained with drug-resistant EMT-6/CTX
(7)
breast carcinomas in a different mouse strain (Fig. 5a
). We therefore sought to determine whether
cyclophosphamide on this schedule was in fact antiangiogenic and, in
particular, whether antiangiogenesis explains the improved control of
tumor growth in drug-resistant Lewis lung carcinoma.
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). The majority of endothelial cells at high concentrations
of 4-HC (10 µg/ml) arrested in G1 and showed
increased apoptosis. Lower concentrations (0.1 µg/ml 4-HC) were
cytostatic and were associated with a prolongation of S phase.
Importantly, when endothelial cell migration is stimulated in
vitro by bFGF, even these lower concentrations (0.1 µg/ml 4HC)
caused a 45% decrease in migration (Fig. 2a
) without
affecting the protein levels of three integrins (data not shown).
Angiogenesis Inhibition in Vivo.
To determine the extent of angiogenesis inhibition caused by either
schedule of cyclophosphamide in vivo, mouse corneas were
implanted with bFGF pellets that stimulated corneal neovascularization
over 6 days (8)
. Therapy with cyclophosphamide was
initiated 24 h after pellet implantation, when limbal dilation and
vascular sprouts first appear. Cyclophosphamide administration
equivalent to one cycle of the antiangiogenic schedule (170
mg/kg x 1 at 24 h) inhibited the area of new
vessel growth by 66 ± 5% (Fig. 2b
).
Treatment with the entire conventional schedule of cyclophosphamide,
i.e., three doses of 150 mg/kg at 24, 72, and 120 h,
resulted in 73 ± 5% inhibition (Fig. 2c
).
Whereas inhibition of corneal angiogenesis did not differ statistically
between the two schedules, valid comparison of the level of inhibition
is limited to 6 days because the bFGF stimulus fades. However, in a
tumor-bearing mouse, this antiangiogenic effect would occur 3.5 times
on the 6-day antiangiogenic schedule in contrast to 1 time on the
21-day conventional schedule.
In Vivo Apoptosis of Endothelial Cells followed by
Apoptosis of Drug-resistant Tumor Cells.
To determine whether cyclophosphamide induced endothelial cell
apoptosis in the tumor bed, we analyzed cell turnover in drug-resistant
tumors. Whereas BrdUrd incorporation of tumor cells was similar in
control and cyclophosphamide-treated mice, endothelial cell and tumor
cell apoptosis revealed marked differences between treatment groups
(Fig. 3
). Untreated drug-resistant Lewis lung carcinomas showed a tumor cell
labeling index of 37%, a low tumor cell apoptotic rate of 1.9%, and
minimal detectable (0.2%) endothelial cell apoptosis. The conventional
schedule of cyclophosphamide generated one broad peak of tumor cell
apoptosis that fell to background levels from day 13 through day 21
after the start of treatment (Fig. 3a
). In contrast, the
antiangiogenic schedule generated four peaks of tumor cell apoptosis
over the 21-day period (Fig. 3b
). Double immunofluorescence
(von Willebrand factor antibody and TUNEL assay) was used to
discriminate endothelial cell apoptosis from tumor cell apoptosis (Fig. 3
). On both schedules, endothelial cell apoptosis from cyclophosphamide
therapy preceded the apoptosis of drug-resistant tumor cells. When
doses of cyclophosphamide were spaced 6 days apart on the
antiangiogenic schedule, endothelial cell apoptosis preceded a
significant increase in tumor cell apoptosis by 3.5 days, suggesting
that the antiendothelial effect of cyclophosphamide is primary and
causative. Because the half-life of cyclophosphamide in mice is less
than 30 min (21
, 22)
, and the BrdUrd incorporation rate of
tumor cells on the antiangiogenic schedule remained at 35% (similar to
untreated controls), the apoptosis of drug-resistant tumor cells on
both schedules most likely resulted from endothelial cell suppression
and not from delayed tumor penetration of activated cyclophosphamide.
Furthermore, these data demonstrate that tumor growth, which occurred
after the first 13 days on the conventional schedule (see Fig. 1a
, inset), was prevented on the antiangiogenic schedule of
cyclophosphamide by more sustained inhibition of angiogenesis within
the tumor bed.
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Drug-resistant Tumor Growth Inhibition by Cyclophosphamide Is Linked to Endothelial Cell p53 |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDrug-resistant Tumor Growth...Eradication of Drug-sensitive...Eradication of Drug-resistant...DISCUSSIONREFERENCES |
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compares the growth of drug-resistant Lewis lung carcinoma
in both types of congenic mice treated on the antiangiogenic schedule
of cyclophosphamide. The growth of drug-resistant tumors in p53+/+ mice
was completely suppressed for at least six 6-day cycles of
cyclophosphamide. In contrast, the growth of drug-resistant tumors in
p53-/- mice was similar to that of untreated control tumors after the
first dose of cyclophosphamide. Tumor cell proliferation and tumor and
endothelial cell apoptosis of these growing tumors in p53-/- mice
also remained equivalent to untreated control tumors until day 6 (Fig. 4b
, left panel). Within 10–20 min after the second dose of
cyclophosphamide on day 6, marked apoptosis of p53-/- endothelial
cells occurred without an increase in the tumor cell apoptotic rate
(Fig. 4b
, middle panel). By 180 min after this second dose,
70–90% of the central mass of these large, cyclophosphamide-resistant
tumors had become necrotic. In the remaining viable cortical rim,
endothelial cell apoptosis and tumor cell apoptosis were progressing
nearly synchronously (Fig. 4b
, right panel). After a third
dose of cyclophosphamide, tumors in the p53-/- mice were eradicated
and did not recur off therapy (Fig. 4a
).
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), elicit an arrest of endothelial cell cycle (see Fig. 2a
), and induce a level of endothelial cell apoptosis (see
Figs. 2a
and 3b
) that results in a balance of
tumor cell proliferation and apoptosis (see Figs. 1a
and 3b
) during the initial 36 days. In contrast, p53-/-
endothelial cells would not undergo an arrest of cell cycle and did not
undergo detectable apoptosis after the first dose of cyclophosphamide
(Fig. 4b
, left panel). This resulted in growth of the
tumor (Fig. 4a
) and documents the drug resistance of
the tumor. After the second dose of cyclophosphamide in p53-/- mice,
p53-independent apoptosis of endothelial cells rapidly engulfed most of
the tumor bed (Fig. 4b
), presumably reflecting the
attainment of cumulative and lethal DNA damage. Thereafter, despite
drug resistance, tumor cells could not evade death resulting from this
extensive endothelial cell apoptosis. The difference in magnitude
(partial versus complete) and timing (4 days
versus 180 min after cyclophosphamide) of drug-resistant
tumor cell apoptosis appeared to be based predominantly on the
endothelial cellular response to cyclophosphamide mediated through p53
(Fig. 4
). Thus, the exquisite control of tumor growth exerted by
endothelial cells is revealed by the ability of cyclophosphamide to
elicit a differential level of endothelial cell apoptosis. In p53+/+
mice, sporadic endothelial cell apoptosis induced by the antiangiogenic
schedule of cyclophosphamide is sufficient to enable drug-resistant
tumor growth suppression. In p53-/- mice, cyclophosphamide causes a
total involution of the vascular bed that leads to the eradication of
drug-resistant tumors comprising 4.5% of body weight. |
Eradication of Drug-sensitive Lewis Lung Carcinoma and L1210 Leukemia by the Antiangiogenic Schedule of Cyclophosphamide |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDrug-resistant Tumor Growth...Eradication of Drug-sensitive...Eradication of Drug-resistant...DISCUSSIONREFERENCES |
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), a similar effect could interfere with the
generation of acquired drug resistance in a drug-sensitive tumor. We
therefore treated the original, drug-sensitive Lewis lung carcinoma
with either the antiangiogenic or conventional schedule of
cyclophosphamide. The antiangiogenic schedule was not only more
effective when compared with the conventional schedule, but therapy
could be discontinued with long-term tumor-free survival (Fig. 1b
). Similar initial tumor burdens of Lewis lung carcinoma
that here and historically (4)
acquired drug resistance on
the conventional schedule did not do so on the antiangiogenic schedule.
We confirmed these observations with a more inherently
cyclophosphamide-sensitive tumor, L1210 leukemia (9)
. Both
the conventional and antiangiogenic schedules of cyclophosphamide were
curative of L1210 leukemia when therapy was initiated at tumor volumes
of 100, 200, and 500 mm3
(data not shown). An
advantage of the antiangiogenic schedule of cyclophosphamide was
revealed when therapy of L1210 tumors was initiated at 1000
mm3
(Fig. 5b
). Whereas 10 of 10 mice harboring 1000
mm3
L1210 tumors developed acquired drug
resistance and died of tumor on the conventional schedule of
cyclophosphamide, 7 of 10 mice (70%) treated with the antiangiogenic
schedule of cyclophosphamide are long-term, tumor-free survivors off
therapy. We interpret this eradication of drug-sensitive Lewis lung
carcinoma and L1210 leukemia as resulting from two actions of
cyclophosphamide: (a) the direct cell kill of drug-sensitive
tumor cells; and (b) the direct cell kill of endothelial
cells, leading to the apoptosis of both drug-sensitive and, more
importantly, drug-resistant tumor cells. |
Eradication of Drug-resistant Lewis Lung Carcinoma by Adding a Second Angiogenesis Inhibitor (TNP-470) to the Antiangiogenic Schedule of Cyclophosphamide |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDrug-resistant Tumor Growth...Eradication of Drug-sensitive...Eradication of Drug-resistant...DISCUSSIONREFERENCES |
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).
All mice had complete regression of drug-resistant Lewis lung
carcinoma, and only 3 of 38 mice (8%) developed recurrent primary
tumor 14–18 days after completion of therapy. Another 3 of 38 mice
(8%) died of toxicity within 10 days of the completion of therapy.
These mice showed no evidence of tumor recurrence; nevertheless, they
had severe ataxia and died despite the administration of parenteral
fluids. These ataxic mice were unevaluable for tumor recurrence and
were considered treatment failures in the total of 38 mice. No tumor
relapses occurred later than 18 days after therapy was
completed. However, sterilization of cages, food, and water by
autoclaving was found to be critical. In two experiments performed
without autoclaving, tumor eradication occurred in 20 of 20 mice, yet
14 of 20 mice developed pulmonary inflammation resulting in premature
death 50 ± 6 days after therapy was completed on day
36. Because no tumors recurred later than 18 days after the completion
of therapy, and these mice had no evidence of primary or metastatic
tumor at the time of death, the drug-resistant tumors in these 14 of 20
mice were considered eradicated. We assume that these late deaths were
in part due to pulmonary endothelial cell damage (20)
and
immunosuppression (4)
by cyclophosphamide complicated by
an acquired infection because late deaths did not occur in the other
three experiments in which we presterilized the food, water, and cages. |
DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDrug-resistant Tumor Growth...Eradication of Drug-sensitive...Eradication of Drug-resistant...DISCUSSIONREFERENCES |
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Angiogenesis, the process of pathological vascular in-growth critical
for tumor expansion, was first proposed as a target for anticancer
therapy in 1971 (28)
. Evidence that a chemotherapeutic
agent directly causes cytotoxicity to the vasculature in a
drug-resistant solid tumor followed in 1991 (29)
. In this
report, Baguley et al. demonstrated that vinblastine led to
greater than 90% necrosis of drug-resistant solid tumors within hours
but had no effect when the same cells were grown as ascites
(29)
. However, because the maximum tolerated dose of
vinblastine was administered, these authors were unable to continue on
an antiangiogenic schedule and thus demonstrate long-term suppression
of drug-resistant tumor growth. In contrast, our strategy was to
optimize the schedule for continued cytotoxic pressure on the
endothelial cells within the vascular bed of the tumor. Optimized
antiangiogenesis renders cyclophosphamide indirectly and repeatedly
capable of killing drug-resistant tumor cells, limits the expression of
clinical resistance, and improves tumor response. Using this closely
cycled dosing schedule, we did not observe the rapid, widespread
vascular collapse and extensive necrosis in wild-type mice seen by
Baguley et al. (29)
with vinblastine and by
Denekamp (30
, 31)
using other therapies. Further, the
3.5-day interval between the onset of endothelial cell apoptosis and
maximum drug-resistant tumor cell apoptosis is inconsistent with
vascular necrosis (see Fig. 3b
). However, the rapid and
nearly synchronous apoptosis of endothelial cells observed in p53-/-
mice harboring drug-resistant tumor treated with the antiangiogenic
schedule of cyclophosphamide may have had an undetected component of
ischemic or hemorrhagic vascular necrosis, as described by Baguley
et al. (29)
and Denekamp (30
, 31)
.
Our antiangiogenic schedule also bears a distant resemblance to "optimal dose" schedules (15) used in therapy of mouse leukemias and solid tumors reported over 30 years ago (3 , 15, 16, 17 , 32 , 33) and to schedules predicted from in vivo tumor cell cycle kinetics (34 , 35) .
Since the report by Baguley et al. (29)
, there
have been numerous reports relating the short-term effects of cytotoxic
chemotherapy on vascular endothelial cells. Antiendothelial effects
have been demonstrated in vitro for cyclophosphamide
(20)
, 5-flurouracil (36)
, and mitomycin C
(36
, 37)
, and short-term antiangiogenic effects have been
demonstrated in vivo for vincristine (38)
,
vinblastine (29
, 38
, 39)
, doxorubicin (38)
,
mitoxantrone (38)
, etoposide (38)
, paclitaxel
(40, 41, 42)
, 6-methylmercaptopurine (43)
,
tegafur (44)
, 9-amino-20(S)-camptothecin
(45)
, topotecan (45)
, camptosar
(45)
, and combretastatin A-4 (46
, 47)
.
However, our data with cyclophosphamide lead us to conclude that
demonstration of antiangiogenic efficacy in short-term assays must now
be followed by determination of a schedule that allows this effect to
be sustainable. Certain agents, as described here for cyclophosphamide,
readily lead to antiangiogenic effects within tumors on different
schedules, and one need only determine the most effective
antiangiogenic schedule. Other agents, as described here for
5-fluorouracil and 6-mercaptopurine (see Fig. 2
), are nearly devoid of
antiangiogenic efficacy when given as bolus injections but reveal a
potent antiangiogenic effect as continuous infusions. At least one
chemotherapeutic, methotrexate, did not possess significant
antiangiogenic efficacy on any schedule that we tested (data not shown;
Ref. 38
), possibly because endothelial cells are reliant
on the salvage pathway for nucleic acids (48)
. We
speculate that certain other chemotherapeutic agents will be
demonstrated to possess an enhanced antiangiogenic capability after
schedule modifications that are dose-dense and range from continuous
infusion to weekly therapy delivered without interruption. Thus, other
cytotoxic chemotherapies, delivered on an antiangiogenic schedule
specific for that agent, may more readily suppress tumor growth in mice
as described here for cyclophosphamide and, by inference from previous
reports (49, 50, 51)
, also for weekly Doxil (see Fig. 2c
).
Because conventional schedules of combination chemotherapy have led to a profound increase in the survival of children with cancer and have improved the survival of adults with certain types of cancer, we do not believe that these clinical protocols should be changed for the sake of increasing the antiangiogenic efficacy of any given drug. Furthermore, it can be argued that our results, in part, may reflect a higher fraction of new, immature vessels present in the rapidly growing, recently established transplantable tumor system used. However, our results in mice may help to explain why some patients who are receiving long-term maintenance or even palliative chemotherapy continue to have stable disease beyond the time that the tumor cells would have been expected to develop drug resistance. Moreover, a closer approximation to antiangiogenic scheduling may explain the improved outcome of empiric treatment of "slower growing" human cancer using continuous infusion 5-fluoururacil (52, 53, 54) , weekly paclitaxel (55, 56, 57) , and daily oral etoposide (58, 59, 60) . If this hypothesis proves generalizable, it may suggest which agents and on which schedules chemotherapy may be best combined with more specific angiogenesis inhibitors for improved antiangiogenic and anticancer efficacy.
ACKNOWLEDGMENTS
We thank Dr. Taturo Udagawa for Western analysis of endothelial
cell integrins and Dr. Philip Linden for the endothelial cell migration
assay.
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FOOTNOTES |
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1 Supported by NIH Grant P01 CA45548 (to J. F.)
and by a grant to Children’s Hospital from EntreMed, Inc. T. B. was a
recipient of an American Cancer Society Clinical Oncology Career
Development award for the first part of these studies. 
2 To whom requests for reprints should be
addressed, at Children’s Hospital, Hunnewell 103, 300 Longwood Avenue,
Boston, MA 02115.
3 The abbreviations used are: bFGF, basic
fibroblast growth factor; 4-HC, 4-hydroxycyclophosphamide; TUNEL,
terminal deoxynucleotidyl transferase-mediated nick end labeling;
BrdUrd, bromodeoxyuridine.
Received 6/22/99. Accepted 2/ 8/00.
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDrug-resistant Tumor Growth...Eradication of Drug-sensitive...Eradication of Drug-resistant...DISCUSSIONREFERENCES |
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B. Laquente, C. Lacasa, M. M. Ginesta, O. Casanovas, A. Figueras, M. Galan, I. G. Ribas, J. R. Germa, G. Capella, and F. Vinals Antiangiogenic effect of gemcitabine following metronomic administration in a pancreas cancer model Mol. Cancer Ther., March 1, 2008; 7(3): 638 - 647. [Abstract] [Full Text] [PDF]
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A. A. Garcia, H. Hirte, G. Fleming, D. Yang, D. D. Tsao-Wei, L. Roman, S. Groshen, S. Swenson, F. Markland, D. Gandara, et al. Phase II Clinical Trial of Bevacizumab and Low-Dose Metronomic Oral Cyclophosphamide in Recurrent Ovarian Cancer: A Trial of the California, Chicago, and Princess Margaret Hospital Phase II Consortia J. Clin. Oncol., January 1, 2008; 26(1): 76 - 82. [Abstract] [Full Text] [PDF]
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J. Ma and D. J. Waxman Modulation of the antitumor activity of metronomic cyclophosphamide by the angiogenesis inhibitor axitinib Mol. Cancer Ther., January 1, 2008; 7(1): 79 - 89. [Abstract] [Full Text] [PDF]
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J. A. Blansfield, D. Caragacianu, H. R. Alexander III, M. A. Tangrea, S. Y. Morita, D. Lorang, P. Schafer, G. Muller, D. Stirling, R. E. Royal, et al. Combining Agents that Target the Tumor Microenvironment Improves the Efficacy of Anticancer Therapy Clin. Cancer Res., January 1, 2008; 14(1): 270 - 280. [Abstract] [Full Text] [PDF]
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P. A. Bunn Jr. and N. Thatcher Introduction Oncologist, January 1, 2008; 13(suppl_1): 1 - 4. [Abstract] [Full Text] [PDF]
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J. Ma and D. J. Waxman Collaboration between hepatic and intratumoral prodrug activation in a P450 prodrug-activation gene therapy model for cancer treatment Mol. Cancer Ther., November 1, 2007; 6(11): 2879 - 2890. [Abstract] [Full Text] [PDF]
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T. J. Kim, M. Ravoori, C. N. Landen, A. A. Kamat, L. Y. Han, C. Lu, Y. G. Lin, W. M. Merritt, N. Jennings, W. A. Spannuth, et al. Antitumor and Antivascular Effects of AVE8062 in Ovarian Carcinoma Cancer Res., October 1, 2007; 67(19): 9337 - 9345. [Abstract] [Full Text] [PDF]
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Y. Shaked and R. S. Kerbel Antiangiogenic Strategies on Defense: On the Possibility of Blocking Rebounds by the Tumor Vasculature after Chemotherapy Cancer Res., August 1, 2007; 67(15): 7055 - 7058. [Abstract] [Full Text] [PDF]
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K. M. Bell-McGuinn, A. L. Garfall, M. Bogyo, D. Hanahan, and J. A. Joyce Inhibition of Cysteine Cathepsin Protease Activity Enhances Chemotherapy Regimens by Decreasing Tumor Growth and Invasiveness in a Mouse Model of Multistage Cancer Cancer Res., August 1, 2007; 67(15): 7378 - 7385. [Abstract] [Full Text] [PDF]
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G. Schaller, I. Fuchs, T. Gonsch, J. Weber, A. Kleine-Tebbe, P. Klare, H.-J. Hindenburg, V. Lakner, A. Hinke, and N. Bangemann Phase II Study of Capecitabine Plus Trastuzumab in Human Epidermal Growth Factor Receptor 2 Overexpressing Metastatic Breast Cancer Pretreated With Anthracyclines or Taxanes J. Clin. Oncol., August 1, 2007; 25(22): 3246 - 3250. [Abstract] [Full Text] [PDF]
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D. Santini, B. Vincenzi, S. Galluzzo, F. Battistoni, L. Rocci, O. Venditti, G. Schiavon, S. Angeletti, F. Uzzalli, M. Caraglia, et al. Repeated Intermittent Low-Dose Therapy with Zoledronic Acid Induces an Early, Sustained, and Long-Lasting Decrease of Peripheral Vascular Endothelial Growth Factor Levels in Cancer Patients Clin. Cancer Res., August 1, 2007; 13(15): 4482 - 4486. [Abstract] [Full Text] [PDF]
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L. Martin and R. Schilder Novel Approaches in Advancing the Treatment of Epithelial Ovarian Cancer: The Role of Angiogenesis Inhibition J. Clin. Oncol., July 10, 2007; 25(20): 2894 - 2901. [Abstract] [Full Text] [PDF]
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P. V. Dickson, J. B. Hamner, T. L. Sims, C. H. Fraga, C. Y.C. Ng, S. Rajasekeran, N. L. Hagedorn, M. B. McCarville, C. F. Stewart, and A. M. Davidoff Bevacizumab-Induced Transient Remodeling of the Vasculature in Neuroblastoma Xenografts Results in Improved Delivery and Efficacy of Systemically Administered Chemotherapy Clin. Cancer Res., July 1, 2007; 13(13): 3942 - 3950. [Abstract] [Full Text] [PDF]
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A. A. Kamat, T. J. Kim, C. N. Landen Jr., C. Lu, L. Y. Han, Y. G. Lin, W. M. Merritt, P. H. Thaker, D. M. Gershenson, F. Z. Bischoff, et al. Metronomic Chemotherapy Enhances the Efficacy of Antivascular Therapy in Ovarian Cancer Cancer Res., January 1, 2007; 67(1): 281 - 288. [Abstract] [Full Text] [PDF]
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B. Dome, M. J.C. Hendrix, S. Paku, J. Tovari, and J. Timar Alternative Vascularization Mechanisms in Cancer: Pathology and Therapeutic Implications Am. J. Pathol., January 1, 2007; 170(1): 1 - 15. [Abstract] [Full Text] [PDF]
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A. Suvannasankha, C. Fausel, B. E. Juliar, C. T. Yiannoutsos, W. B. Fisher, R. H. Ansari, L. L. Wood, G. G. Smith, L. D. Cripe, and R. Abonour Final Report of Toxicity and Efficacy of a Phase II Study of Oral Cyclophosphamide, Thalidomide, and Prednisone for Patients with Relapsed or Refractory Multiple Myeloma: A Hoosier Oncology Group Trial, HEM01-21 Oncologist, January 1, 2007; 12(1): 99 - 106. [Abstract] [Full Text] [PDF]
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K. Podar, G. Tonon, M. Sattler, Y.-T. Tai, S. LeGouill, H. Yasui, K. Ishitsuka, S. Kumar, R. Kumar, L. N. Pandite, et al. The small-molecule VEGF receptor inhibitor pazopanib (GW786034B) targets both tumor and endothelial cells in multiple myeloma PNAS, December 19, 2006; 103(51): 19478 - 19483. [Abstract] [Full Text] [PDF]
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M. R. Horsman and D. W. Siemann Pathophysiologic Effects of Vascular-Targeting Agents and the Implications for Combination with Conventional Therapies Cancer Res., December 15, 2006; 66(24): 11520 - 11539. [Abstract] [Full Text] [PDF]
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L. G. Burdelya, E. A. Komarova, J. E. Hill, T. Browder, N. D. Tararova, L. Mavrakis, P. E. DiCorleto, J. Folkman, and A. V. Gudkov Inhibition of p53 Response in Tumor Stroma Improves Efficacy of Anticancer Treatment by Increasing Antiangiogenic Effects of Chemotherapy and Radiotherapy in Mice Cancer Res., October 1, 2006; 66(19): 9356 - 9361. [Abstract] [Full Text] [PDF]
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R. Buckstein, R. S. Kerbel, Y. Shaked, R. Nayar, C. Foden, R. Turner, C. R. Lee, D. Taylor, L. Zhang, S. Man, et al. High-Dose Celecoxib and Metronomic "Low-dose" Cyclophosphamide Is an Effective and Safe Therapy in Patients with Relapsed and Refractory Aggressive Histology Non-Hodgkin's Lymphoma Clin. Cancer Res., September 1, 2006; 12(17): 5190 - 5198. [Abstract] [Full Text] [PDF]
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Y. Zhang, L. Xiang, R. Hassan, C. H. Paik, J. A. Carrasquillo, B.-s. Jang, N. Le, M. Ho, and I. Pastan Synergistic Antitumor Activity of Taxol and Immunotoxin SS1P in Tumor-Bearing Mice Clin. Cancer Res., August 1, 2006; 12(15): 4695 - 4701. [Abstract] [Full Text] [PDF]
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S. S.W. Ng, A. Sparreboom, Y. Shaked, C. Lee, S. Man, N. Desai, P. Soon-Shiong, W. D. Figg, and R. S. Kerbel Influence of Formulation Vehicle on Metronomic Taxane Chemotherapy: Albumin-Bound versus Cremophor EL-Based Paclitaxel. Clin. Cancer Res., July 15, 2006; 12(14): 4331 - 4338. [Abstract] [Full Text] [PDF]
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R. Saito, M. T. Krauze, C. O. Noble, D. C. Drummond, D. B. Kirpotin, M. S. Berger, J. W. Park, and K. S. Bankiewicz Convection-enhanced delivery of Ls-TPT enables an effective, continuous, low-dose chemotherapy against malignant glioma xenograft model Neuro-oncol, July 1, 2006; 8(3): 205 - 214. [Abstract] [Full Text] [PDF]
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M. F. McCarty and K. I. Block Toward a Core Nutraceutical Program for Cancer Management Integr Cancer Ther, June 1, 2006; 5(2): 150 - 171. [Abstract] [PDF]
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S. D. Young, M. Whissell, J. C.S. Noble, P. O. Cano, P. G. Lopez, and C. J. Germond Phase II Clinical Trial Results Involving Treatment with Low-Dose Daily Oral Cyclophosphamide, Weekly Vinblastine, and Rofecoxib in Patients with Advanced Solid Tumors. Clin. Cancer Res., May 15, 2006; 12(10): 3092 - 3098. [Abstract] [Full Text] [PDF]
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R. Munoz, S. Man, Y. Shaked, C. R. Lee, J. Wong, G. Francia, and R. S. Kerbel Highly Efficacious Nontoxic Preclinical Treatment for Advanced Metastatic Breast Cancer Using Combination Oral UFT-Cyclophosphamide Metronomic Chemotherapy. Cancer Res., April 1, 2006; 66(7): 3386 - 3391. [Abstract] [Full Text] [PDF]
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E. Naumova, P. Ubezio, A. Garofalo, P. Borsotti, L. Cassis, E. Riccardi, E. Scanziani, S. A. Eccles, M. R. Bani, and R. Giavazzi The Vascular Targeting Property of Paclitaxel Is Enhanced by SU6668, a Receptor Tyrosine Kinase Inhibitor, Causing Apoptosis of Endothelial Cells and Inhibition of Angiogenesis. Clin. Cancer Res., March 15, 2006; 12(6): 1839 - 1849. [Abstract] [Full Text] [PDF]
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Y. Jounaidi, C.-S. Chen, G. J. Veal, and D. J. Waxman Enhanced antitumor activity of P450 prodrug-based gene therapy using the low Km cyclophosphamide 4-hydroxylase P450 2B11. Mol. Cancer Ther., March 1, 2006; 5(3): 541 - 555. [Abstract] [Full Text] [PDF]
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U. Emmenegger, G. C. Morton, G. Francia, Y. Shaked, M. Franco, A. Weinerman, S. Man, and R. S. Kerbel Low-Dose Metronomic Daily Cyclophosphamide and Weekly Tirapazamine: A Well-Tolerated Combination Regimen with Enhanced Efficacy That Exploits Tumor Hypoxia Cancer Res., February 1, 2006; 66(3): 1664 - 1674. [Abstract] [Full Text] [PDF]
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J. M. du Manoir, G. Francia, S. Man, M. Mossoba, J. A. Medin, A. Viloria-Petit, D. J. Hicklin, U. Emmenegger, and R. S. Kerbel Strategies for Delaying or Treating In vivo Acquired Resistance to Trastuzumab in Human Breast Cancer Xenografts Clin. Cancer Res., February 1, 2006; 12(3): 904 - 916. [Abstract] [Full Text] [PDF]
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D. A. Reardon, M. J. Egorin, J. A. Quinn, J. N. Rich Sr, I. Gururangan, J. J. Vredenburgh, A. Desjardins, S. Sathornsumetee, J. M. Provenzale, J. E. Herndon II, et al. Phase II Study of Imatinib Mesylate Plus Hydroxyurea in Adults With Recurrent Glioblastoma Multiforme J. Clin. Oncol., December 20, 2005; 23(36): 9359 - 9368. [Abstract] [Full Text] [PDF]
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Y. Shaked, U. Emmenegger, S. Man, D. Cervi, F. Bertolini, Y. Ben-David, and R. S. Kerbel Optimal biologic dose of metronomic chemotherapy regimens is associated with maximum antiangiogenic activity Blood, November 1, 2005; 106(9): 3058 - 3061. [Abstract] [Full Text] [PDF]
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L. Hu, J. Hofmann, J. Holash, G. D. Yancopoulos, A. K. Sood, and R. B. Jaffe Vascular Endothelial Growth Factor Trap Combined with Paclitaxel Strikingly Inhibits Tumor and Ascites, Prolonging Survival in a Human Ovarian Cancer Model Clin. Cancer Res., October 1, 2005; 11(19): 6966 - 6971. [Abstract] [Full Text] [PDF]
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R. Yap, D. Veliceasa, U. Emmenegger, R. S. Kerbel, L. M. McKay, J. Henkin, and O. V. Volpert Metronomic Low-Dose Chemotherapy Boosts CD95-Dependent Antiangiogenic Effect of the Thrombospondin Peptide ABT-510: A Complementation Antiangiogenic Strategy Clin. Cancer Res., September 15, 2005; 11(18): 6678 - 6685. [Abstract] [Full Text] [PDF]
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Y. Shaked, U. Emmenegger, G. Francia, L. Chen, C. R. Lee, S. Man, A. Paraghamian, Y. Ben-David, and R. S. Kerbel Low-dose Metronomic Combined with Intermittent Bolus-dose Cyclophosphamide Is an Effective Long-term Chemotherapy Treatment Strategy Cancer Res., August 15, 2005; 65(16): 7045 - 7051. [Abstract] [Full Text] [PDF]
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C. J. Streck, P. V. Dickson, C. Y.C. Ng, J. Zhou, J. T. Gray, A. C. Nathwani, and A. M. Davidoff Adeno-Associated Virus Vector-Mediated Systemic Delivery of IFN-{beta} Combined with Low-Dose Cyclophosphamide Affects Tumor Regression in Murine Neuroblastoma Models Clin. Cancer Res., August 15, 2005; 11(16): 6020 - 6029. [Abstract] [Full Text] [PDF]
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D. S. Riddick, C. Lee, S. Ramji, E. C. Chinje, R. L. Cowen, K. J. Williams, A. V. Patterson, I. J. Stratford, C. S. Morrow, A. J. Townsend, et al. CANCER CHEMOTHERAPY AND DRUG METABOLISM Drug Metab. Dispos., August 1, 2005; 33(8): 1083 - 1096. [Abstract] [Full Text] [PDF]
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G. Bocci, M. Tuccori, U. Emmenegger, V. Liguori, A. Falcone, R. S. Kerbel, and M. Del Tacca Cyclophosphamide-methotrexate 'metronomic' chemotherapy for the palliative treatment of metastatic breast cancer. A comparative pharmacoeconomic evaluation Ann. Onc., August 1, 2005; 16(8): 1243 - 1252. [Abstract] [Full Text] [PDF]
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E. di Tomaso, D. Capen, A. Haskell, J. Hart, J. J. Logie, R. K. Jain, D. M. McDonald, R. Jones, and L. L. Munn Mosaic Tumor Vessels: Cellular Basis and Ultrastructure of Focal Regions Lacking Endothelial Cell Markers Cancer Res., July 1, 2005; 65(13): 5740 - 5749. [Abstract] [Full Text] [PDF]
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G. Li, L. Tian, J.-m. Hou, Z.-y. Ding, Q.-m. He, P. Feng, Y.-j. Wen, F. Xiao, B. Yao, R. Zhang, et al. Improved Therapeutic Effectiveness by Combining Recombinant CXC Chemokine Ligand 10 with Cisplatin in Solid Tumors Clin. Cancer Res., June 1, 2005; 11(11): 4217 - 4224. [Abstract] [Full Text] [PDF]
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P. E. Huber, M. Bischof, J. Jenne, S. Heiland, P. Peschke, R. Saffrich, H.-J. Grone, J. Debus, K. E. Lipson, and A. Abdollahi Trimodal Cancer Treatment: Beneficial Effects of Combined Antiangiogenesis, Radiation, and Chemotherapy Cancer Res., May 1, 2005; 65(9): 3643 - 3655. [Abstract] [Full Text] [PDF]
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P. Beaudry, J. Force, G. N. Naumov, A. Wang, C. H. Baker, A. Ryan, S. Soker, B. E. Johnson, J. Folkman, and J. V. Heymach Differential Effects of Vascular Endothelial Growth Factor Receptor-2 Inhibitor ZD6474 on Circulating Endothelial Progenitors and Mature Circulating Endothelial Cells: Implications for Use as a Surrogate Marker of Antiangiogenic Activity Clin. Cancer Res., May 1, 2005; 11(9): 3514 - 3522. [Abstract] [Full Text] [PDF]
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R. Okamoto, M. Ueno, Y. Yamada, N. Takahashi, H. Sano, T. Suda, and N. Takakura Hematopoietic cells regulate the angiogenic switch during tumorigenesis Blood, April 1, 2005; 105(7): 2757 - 2763. [Abstract] [Full Text] [PDF]
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B. P. Schneider and K. D. Miller Angiogenesis of Breast Cancer J. Clin. Oncol., March 10, 2005; 23(8): 1782 - 1790. [Full Text] [PDF]
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R. W. Moss Patient Perspectives: Tijuana Cancer Clinics in the Post-NAFTA Era Integr Cancer Ther, March 1, 2005; 4(1): 65 - 86. [Abstract] [PDF]
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V. Y. Gorbacheva, R. V. Kondratov, R. Zhang, S. Cherukuri, A. V. Gudkov, J. S. Takahashi, and M. P. Antoch From The Cover: Circadian sensitivity to the chemotherapeutic agent cyclophosphamide depends on the functional status of the CLOCK/BMAL1 transactivation complex PNAS, March 1, 2005; 102(9): 3407 - 3412. [Abstract] [Full Text] [PDF]
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T. E. Sutherland, M. Schuliga, T. Harris, B. L. Eckhardt, R. L. Anderson, L. Quan, and A. G. Stewart 2-Methoxyestradiol Is an Estrogen Receptor Agonist That Supports Tumor Growth in Murine Xenograft Models of Breast Cancer Clin. Cancer Res., March 1, 2005; 11(5): 1722 - 1732. [Abstract] [Full Text] [PDF]
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G. Gasparini, R. Longo, M. Fanelli, and B. A. Teicher Combination of Antiangiogenic Therapy With Other Anticancer Therapies: Results, Challenges, and Open Questions J. Clin. Oncol., February 20, 2005; 23(6): 1295 - 1311. [Abstract] [Full Text] [PDF]
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K. Podar and K. C. Anderson The pathophysiologic role of VEGF in hematologic malignancies: therapeutic implications Blood, February 15, 2005; 105(4): 1383 - 1395. [Abstract] [Full Text] [PDF]
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K. Pietras and D. Hanahan A Multitargeted, Metronomic, and Maximum-Tolerated Dose "Chemo-Switch" Regimen is Antiangiogenic, Producing Objective Responses and Survival Benefit in a Mouse Model of Cancer J. Clin. Oncol., February 10, 2005; 23(5): 939 - 952. [Abstract] [Full Text] [PDF]
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D. J. Hicklin and L. M. Ellis Role of the Vascular Endothelial Growth Factor Pathway in Tumor Growth and Angiogenesis J. Clin. Oncol., February 10, 2005; 23(5): 1011 - 1027. [Abstract] [Full Text] [PDF]
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H.-P. Gerber and N. Ferrara Pharmacology and Pharmacodynamics of Bevacizumab as Monotherapy or in Combination with Cytotoxic Therapy in Preclinical Studies Cancer Res., February 1, 2005; 65(3): 671 - 680. [Abstract] [Full Text] [PDF]
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V. R. Rozados, A. M. Sanchez, S. I. Gervasoni, H. H. Berra, P. Matar, and O. Graciela Scharovsky Metronomic therapy with cyclophosphamide induces rat lymphoma and sarcoma regression, and is devoid of toxicity Ann. Onc., October 1, 2004; 15(10): 1543 - 1550. [Abstract] [Full Text] [PDF]
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 E. Khmelewski, A. Becker, T. Meinertz, and W. D. Ito Tissue Resident Cells Play a Dominant Role in Arteriogenesis and Concomitant Macrophage Accumulation Circ. Res., September 17, 2004; 95(6): e56 - e64. [Abstract] [Full Text] [PDF]
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G. Bocci, S. Man, S. K. Green, G. Francia, J. M. L. Ebos, J. M. du Manoir, A. Weinerman, U. Emmenegger, L. Ma, P. Thorpe, et al. Increased Plasma Vascular Endothelial Growth Factor (VEGF) as a Surrogate Marker for Optimal Therapeutic Dosing of VEGF Receptor-2 Monoclonal Antibodies Cancer Res., September 15, 2004; 64(18): 6616 - 6625. [Abstract] [Full Text] [PDF]
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F. Donate, J. C. Juarez, X. Guan, N. V. Shipulina, M. L. Plunkett, Z. Tel-Tsur, D. E. Shaw, W. T. Morgan, and A. P. Mazar Peptides Derived from the Histidine-Proline Domain of the Histidine-Proline-Rich Glycoprotein Bind to Tropomyosin and Have Antiangiogenic and Antitumor Activities Cancer Res., August 15, 2004; 64(16): 5812 - 5817. [Abstract] [Full Text] [PDF]
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G. Kaur, D. Belotti, A. M. Burger, K. Fisher-Nielson, P. Borsotti, E. Riccardi, J. Thillainathan, M. Hollingshead, E. A. Sausville, and R. Giavazzi Antiangiogenic Properties of 17-(Dimethylaminoethylamino)-17-Demethoxygeldanamycin: An Orally Bioavailable Heat Shock Protein 90 Modulator Clin. Cancer Res., July 15, 2004; 10(14): 4813 - 4821. [Abstract] [Full Text] [PDF]
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J. J. Raizer, M. G. Malkin, M. Kleber, and L. E. Abrey Phase 1 study of 28-day, low-dose temozolomide and BCNU in the treatment of malignant gliomas after radiation therapy Neuro-oncol, July 1, 2004; 6(3): 247 - 252. [Abstract] [PDF]
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S. De Placido, G. Scambia, G. Di Vagno, E. Naglieri, A. V. Lombardi, R. Biamonte, M. Marinaccio, G. Carteni, L. Manzione, A. Febbraro, et al. Topotecan Compared With No Therapy After Response to Surgery and Carboplatin/Paclitaxel in Patients With Ovarian Cancer: Multicenter Italian Trials in Ovarian Cancer (MITO-1) Randomized Study J. Clin. Oncol., July 1, 2004; 22(13): 2635 - 2642. [Abstract] [Full Text] [PDF]
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R. T. Tong, Y. Boucher, S. V. Kozin, F. Winkler, D. J. Hicklin, and R. K. Jain Vascular Normalization by Vascular Endothelial Growth Factor Receptor 2 Blockade Induces a Pressure Gradient Across the Vasculature and Improves Drug Penetration in Tumors Cancer Res., June 1, 2004; 64(11): 3731 - 3736. [Abstract] [Full Text] [PDF]
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U. Emmenegger, S. Man, Y. Shaked, G. Francia, J. W. Wong, D. J. Hicklin, and R. S. Kerbel A Comparative Analysis of Low-Dose Metronomic Cyclophosphamide Reveals Absent or Low-Grade Toxicity on Tissues Highly Sensitive to the Toxic Effects of Maximum Tolerated Dose Regimens Cancer Res., June 1, 2004; 64(11): 3994 - 4000. [Abstract] [Full Text] [PDF]
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J. W. Park, R. S. Kerbel, G. J. Kelloff, J. C. Barrett, B. A. Chabner, D. R. Parkinson, J. Peck, R. W. Ruddon, C. C. Sigman, and D. J. Slamon Rationale for Biomarkers and Surrogate End Points in Mechanism-Driven Oncology Drug Development Clin. Cancer Res., June 1, 2004; 10(11): 3885 - 3896. [Full Text] [PDF]
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E. Bergsland and M. N. Dickler Maximizing the Potential of Bevacizumab in Cancer Treatment Oncologist, June 1, 2004; 9(suppl_1): 36 - 42. [Abstract] [Full Text] [PDF]
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H. S. Rugo Bevacizumab in the Treatment of Breast Cancer: Rationale and Current Data Oncologist, June 1, 2004; 9(suppl_1): 43 - 49. [Abstract] [Full Text] [PDF]
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x neovessel length x clock
hours of neovessels. The percentage of inhibition was calculated by
normalizing the area of neovascularization in treated mice to the area
of neovascularization in saline-treated controls
(n = 8 mice/group). The experiment was
repeated three times with similar results. c, relative
inhibition of the area of corneal neovascularization and
schedule-dependent antiangiogenic efficacy of cyclophosphamide and
other chemotherapeutic agents as detailed in "Materials and
Methods." Continuous infusion of the antimetabolites (5-fluorouracil
and 6-mercaptopurine ribose phosphate) demonstrated superior inhibition
of growth factor-induced angiogenesis when compared with equivalent
bolus injections. Likewise, the pegylated liposomal formulation of
doxorubicin enhanced the antiangiogenic efficacy of an equivalent dose
of doxorubicin (see "Discussion").
, control saline; 
, conventional schedule [150
mg/kg every other day for three doses (white arrows,
total 450 mg/kg) every 21 days]; •, antiangiogenic schedule (170
mg/kg every 6 days, CTX, thin black
arrows); 
, antiangiogenic schedule of cyclophosphamide and
TNP-470 (170 mg/kg cyclophosphamide and 12.5 mg/kg TNP-470 administered
on the same day of the 6-day cycle for seven cycles, CTX + TNP, thick black arrows). The
inset (top right) has magnified axes for
the first 21 days of therapy (n = 6
mice/group). All control and conventional schedule-treated mice
died with large tumor burdens. Therapy was discontinued on the
antiangiogenic schedule of cyclophosphamide alone after two of six mice
died with pulmonary inflammation, accompanied by high peripheral
leukocyte counts. No mouse on either schedule had visibly detectable
pulmonary metastases at time of death. Therapy was discontinued on the
antiangiogenic schedule of cyclophosphamide plus TNP-470 after seven
cycles, three cycles beyond the point at which tumors were no longer
visible. This graph depicts the long-term survival of five of six mice
treated with the antiangiogenic schedule of cyclophosphamide and
TNP-470 in one of five separate experiments. The
arrow and Note on the graph reflect the
recurrence of one of six drug-resistant tumors at 18 days off therapy
in this experiment. b, antiangiogenic
versus conventional scheduling of cyclophosphamide for
drug-sensitive Lewis lung carcinoma. 
