| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Clinical Trials |
Medicine Branch [W. H. W., W. D. F., K. B., A. M. S.], Laboratory of Pathology [L. S., E. K. M., M. R.], Pediatric Oncology Branch [K. E. W., F. M. B.], and Developmental Therapeutic Program [E. S., A. M. S., A. M.], National Cancer Institute, Bethesda, Maryland 20892
 |
ABSTRACT |
|---|
 Top ABSTRACT INTRODUCTIONCASE REPORTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
|
INTRODUCTION |
|---|
|
TopABSTRACTINTRODUCTIONCASE REPORTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
We are in the early clinical development of UCN-012 (NSC 638850), a protein kinase inhibitor with some selectivity for protein kinase C and cdk-1 but whose most important cellular targets remain uncertain (6, 7, 8, 9, 10, 11) . In human tumor cells, UCN-01 displays synergy with chemotherapy and increases chemotherapy-induced apoptosis at concentrations which are noncytotoxic (10, 11, 12, 13) . In this report, we present the clinical case of a patient with resistant lymphoma who failed to respond to UCN-01 alone but achieved a complete remission after one cycle of UCN-01 and EPOCH chemotherapy. Previous studies in vitro have shown that UCN-01 can abrogate the S and G2 checkpoints and that it increases the cytotoxicity of DNA-damaging agents and apoptosis (7 , 8 , 10 , 11 , 13 , 14) . This case report provides clinical evidence for the enhancement of chemotherapy cytotoxicity by UCN-01 and suggests that modulation of cell-cycle checkpoints may reduce the threshold for apoptosis.
|
CASE REPORT |
|---|
|
TopABSTRACTINTRODUCTIONCASE REPORTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Approximately 10 months later, the patient developed progressive neutropenia (absolute neutrophil count <500 cells/µl) and thrombocytopenia with an elevated LDH. CT scans showed progressive splenomegaly and adenopathy, and bone marrow biopsies showed lymphoma with moderate hyperplasia and increased megakaryocytes. He underwent a therapeutic splenectomy and recovered his neutrophil (>1,000 cells/µl) and platelet (>150,000/µl) counts over the next 4 days, and the LDH returned to normal. On pathological review, the spleen showed histological transformation to a large B cell lymphoma. Over the next 2 months, the patient developed elevated hepatic enzymes (up to five times the normal amount), and a liver biopsy showed large B cell lymphoma.
Therapeutic options were discussed and the patient elected to receive UCN-01 (53 mg/m2/day for 72 h) on a phase I protocol. He acutely tolerated the first cycle of UCN-01 but was admitted to the hospital 4 weeks later with profound fatigue and dehydration. Hematological evaluation showed anemia (hemoglobin, 5.5) and thrombocytopenia (37,000 platelets/µl) with a normal neutrophil count (5,350 cells/µl), and blood chemistries showed an increase in alkaline phosphatase (252 units/L), bilirubin (1.8 mg/dl), and LDH (638 units/L; normal, <225 units/L). CT showed progressive hepatomegaly and diffuse adenopathy, and a bone marrow biopsy showed diffuse replacement with large B cell lymphoma. Due to rapidly worsening disease, the patient received modified doses of "standard" EPOCH chemotherapy; because of the recent UCN-01 and liver abnormalities, cyclophosphamide was omitted and vincristine was administered at 75% dose (16) . A total dose (mg/m2) of 40 doxorubicin, 200 etoposide, and 1.2 vincristine was administered as continuous infusions over 96 h, and 60 prednisone was administered p.o. for 5 days. G-CSF (5 µg/kg, s.c. twice per day) was begun 24 h after chemotherapy. Laboratory studies on treatment day 1 were LDH, 1,358 units/L; total bilirubin, 9.7 mg/dl (direct, 6.8); and absolute neutrophil count, 5,520 cells/µl. On day 3, the LDH increased to 5,851 units/L, and the total bilirubin had decreased to 2.8 mg/dl. By day 7, the LDH had normalized, but the patient became neutropenic and was transferred to the intensive care unit with fever and hypotension. Evaluation revealed a tender abdomen and CT showed a diffusely thickened bowel consistent with neutropenic enterocolitis. Blood cultures showed Candida krusei, and the patient remained unstable despite broad spectrum antibiotics, blood pressure support, and intubation. Although the neutrophils recovered by day 16, the patient expired on day 23 from uncontrolled C. sepsis. An autopsy was obtained.
|
MATERIALS AND METHODS |
|---|
|
TopABSTRACTINTRODUCTIONCASE REPORTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Molecular Analysis.
Formalin-fixed paraffin-embedded tissue samples were sectioned,
digested in a buffer (50 mM Tris (pH 8.0), 150
mM NaCl, 5 mM EDTA, 1% SDS) containing
proteinase K (Life Technologies, Inc., Rockville, MD) and RNase A
(Sigma, St. Louis, MO), and incubated at 55°C for 48–72 h. When
digestion was complete, DNA was purified by phenol/chloroform
extraction and precipitated with ammonium acetate (5.0
M) and 100% ethanol (17)
. The pellets
were dried and then dissolved in double-distilled water, and the DNA
was quantitated by absorbance at 260 nm.
To determine clonality of the IgH gene, PCR assays were performed on each sample using the VH framework 3 and JH consensus primers as reported by Segal et al. (18) . PCR was performed using 1 µg of DNA template in 1x PCR buffer [10 mM Tris-HCl, 50 mM KCl, 2.5 mM MgCl2, 200 µmol/L deoxynucleotide triphosphates (each), and 0.5 µmol/L primers (each)]. The reaction was initiated with 0.5 U of Taq polymerase LD (Perkin-Elmer-Cetus, Norwalk, CT) treated with TaqStart antibody (Clontech Laboratories, Palo Alto, CA), and PCR was continued for 35 cycles (94°C, 1 min; 56°C, 1 min; and 74°C, 1 min) with a final extension of 7 min at 74°C (19) . Subsequent to amplification, the products were separated by 16% nondenaturing PAGE (Bio-Rad, Richmond, CA) and visualized by UV light after ethidium bromide treatment. Control PCR to glyceraldehyde phosphate dehydrogenase was also performed to assess the integrity of extracted DNA for amplification.
Pharmacokinetics.
Blood samples were obtained for UCN-01 analysis at 0, 4, 12, 24, 48,
and 72 h from the start of the UCN-01 infusion and at 2, 12, and
24 h and 21 days from the end of the infusion. Samples were also
obtained at 34, 36, 38, 46, and 48 days from the start of the UCN-01
infusion, which corresponded to 0, 48, and 96 h and 12 and 14 days
from the start of the EPOCH infusion. Saliva samples for UCN-01
determination were obtained at 24 and 48 h from the start of the
UCN-01 infusion and on days 24, 31, and 33 from the end of the UCN-01
infusion. The latter two saliva samples corresponded to 0 and 48 h
from the start of the EPOCH infusion. Pharmacokinetic parameters for
UCN-01 were obtained by fitting a two-compartment open linear model to
the data. These calculations were made with the use of ADAPT II using a
weighted least squares estimator. These parameters were calculated
using data collected before the initiation of EPOCH chemotherapy. The
changes in pharmacokinetic parameters were estimated assuming an
instantaneous change in clearance and volume of distribution during the
EPOCH infusion.
UCN-01 concentrations were determined by reverse-phase HPLC using the Hewlett Packard 1090 series II liquid chromatograph equipped with a photodiode-array detector and an HP 1046A programmable fluorescence detector (Hewlett-Packard, Palo Alto, CA). Calibration curves of 4–200 ng/ml and 200–20,000 ng/ml were prepared for the determination of UCN-01 from saliva and plasma, respectively. A sample of 250 µl of either plasma or saliva was prepared by protein precipitation with 1.0 ml of acetonitrile. Umbelliferone was added as the internal standard. Separation was performed using a Waters Corp. (Milford, MA) Nova-Pak Phenyl 3.9 x 150 mm column. The mobile phase of acetonitrile and 0.05 M ammonium acetate (pH 4.15) was pumped at a flow rate of 1.0 ml/min using a gradient profile. The total run time was 20 min per sample. UCN-01 was quantitated using fluorescence detection for saliva samples. The excitation and emission wavelengths monitored were 290 nm and 400 nm, respectively. UCN-01 was quantitated using UV absorption for plasma samples. UCN-01 was detected at 295 nm, and umbelliferone was detected at 323 nm.
Doxorubicin (Sigma) concentration was measured by an isocratic
reverse-phase HPLC method with fluorescence detection. Daunorubicin was
added as an internal standard. Plasma samples were prepared by solid
phase extraction and eluted with 9:1 methanol:formic acid. CSF samples
were extracted with 5% perchloric acid. The mobile phase consisted of
79:21 0.4 M ammonium formate:acetonitrile at pH 4.0 and a
flow rate of 2 ml/min. An excitation wavelength of 480 nM
and emission wavelength of 595 nM were used for
fluorescence detection. A µBondapak Phenyl column (Waters Corp.) with
a PS-GU Phenyl 5-µ guard column (Thomson Instrument Company,
Springfield, VA) was used. Analysis was done using Millenium software
(Waters Corp.). The limit of detection was 5 nM, limit of
quantitation was 10 nM, and coefficient of variation was
10%. Etoposide was quantitated using a previously published
reverse-phase HPLC method (20)
. A C18 column was used for
separation and UV detection at 254 nm. The standard curves ranged
between 500 ng/ml and 30,000 ng/ml with coefficients of variation
<20%.
|
RESULTS |
|---|
|
TopABSTRACTINTRODUCTIONCASE REPORTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
phenotype. Repeat bone marrow biopsies obtained 1 and
6 months after EPOCH II showed a similar extent of involvement by a
low-grade B cell lymphoma. Histological assessment of the spleen,
liver, and bone marrow 
1 year after EPOCH II showed diffuse
involvement by small and large B cell lymphoma consistent with
transformation to diffuse large B cell lymphoma. A bone marrow biopsy
obtained immediately after UCN-01 also showed diffuse replacement by
small and large B cell lymphoma. At the time of autopsy, multiple tissues were examined by histology and immunohistochemistry. Sections of the liver showed periportal fibrosis, mild chronic inflammation, cholestasis with bile plugging, and microvesicular hepatocellular steatosis but no evidence of tumor. The bone marrow was markedly hypocellular with scattered small CD3+ T cells and no evidence of L26+ B cells or lymphoma. Interestingly, sections of lymph nodes showed near complete lymphocyte depletion with fibrosis, vascular dilation, and prominent hemosiderin deposition. Nearly all remaining viable lymphocytes stained with CD3 and no L26+ B cells were present. Sections from retroperitoneal lymph nodes showed large, amorphous, hyalinized areas. No other organs or tissues examined showed histological evidence of lymphoma.
Pharmacokinetics.
The patient received a single cycle of UCN-01 at 53
mg/m2/day infused over 72 h on our phase I
study. This dose exceeded the maximum tolerated dose, which was limited
by hyperglycemia, nausea and vomiting, and hypoxia. Pharmacokinetic
results from prior patients showed UCN-01 to be highly protein bound
(>99%) and hence to have a prolonged half-life. The present patient
achieved an end infusion UCN-01 concentration of 25,970 ng/ml (48
µmol/L) with a terminal phase rate constant of 0.0003 L/h and a
terminal T1/2 > 1,000 h (>40 days; Fig. 1
). Due to the long T1/2
of UCN-01, a reasonably high UCN-01 concentration of 17,449 ng/ml (36
µmol/L) was present on the first day of EPOCH administration, 34 days
after beginning the UCN-01. Of potential significance, the terminal
phase rate constant appeared to transiently increase to 0.0043 L/h
after the start of EPOCH but returned to the preexistent rate based on
serum samples obtained 8 days after completion of EPOCH.
|
-glycoprotein in salivary
secretions (6)
. The accuracy of saliva concentrations is
currently being validated in other samples by comparison to a
high-speed centrifugation technique for the measurement of free drug in
serum. In the present patient, the saliva concentration was 99.5 ng/ml
(206 nmol/L) at 48 h, 33.5 ng/ml (69 nmol/L) at 27 days, and 10.7
ng/ml (22 nmol/L) at 34 days after the start of the UCN-01
infusion (Fig. 2)
. On the second day of
EPOCH administration (36 days after UCN-01 initiation), the saliva
concentration of UCN-01 was 22 ng/ml (46 nmol/L), which is within the
range (10–40 nmol/L) of UCN-01 observed to abrogate the
G2 checkpoint and to be synergistic with
chemotherapy in vitro (10, 11, 12, 13)
.
|
Molecular Analysis.
IgH PCR assays were performed to assess the presence of minimal
residual disease. Fig. 2
shows the presence of a strong monoclonal band
of identical size in all premortem biopsies from the lymph node,
spleen, and liver. At autopsy, faint monoclonal bands could still be
generated from two of six lymph nodes but not from the liver;
amplifiable DNA was not present in the bone marrow samples. To confirm
the identity of the "monoclonal" bands from the positive tissues,
they were sequenced and found to be identical (data not shown). The
low-level expression and the absence of immunohistochemically
detectable B cells (see below) suggest the presence of few if any
viable tumor cells.
Effects on B and T Cells.
The striking effect of UCN-01 and EPOCH on the patients’ lymphoma
suggested the combination might be quite toxic to normal lymphocytes as
well. To help assess this, we performed immunohistochemistry using B
cell (L26) and T cell (CD3) antibodies and immunoglobulin and T cell
gene rearrangements by PCR on bone marrow, spleen, liver, and lymph
nodes. At autopsy, the lymph nodes only showed scattered T cells and no
B cells by immunohistochemistry. In addition, Fig. 2
shows that the
initial lymph node biopsy and the spleen had a typical polyclonal
immunoglobulin ladder background consistent with normal B cells,
whereas the lymph nodes obtained at autopsy lacked the polyclonal
ladder, indicating significant loss of normal B cells.
We also studied the effect of UCN-01 and EPOCH on the patient’s
peripheral blood lymphocytes. Before beginning any therapy, the patient
had a moderately reduced absolute lymphocyte count of 1,332 cells/µl;
the phenotype of these included 345 CD4 [the majority of which (323)
were CD45RO], 204 CD8, 339 NK cells, and 286 B cells. Although the
patient began EPOCH II with low peripheral lymphocyte counts, he
generally recovered to his baseline counts by the end of each cycle
(Fig. 3A)
. Furthermore, there
was no significant change in the peripheral lymphocyte count by day 28
after administration of UCN-01 (Fig. 3B)
. However, it is of
interest that he had a dramatic reduction in peripheral lymphocytes
from a baseline of 1,160 down to 50 cells/µl by day 7 after EPOCH.
Unexpectedly, he had no evidence of peripheral lymphocyte recovery by
day 23 of EPOCH, despite a brisk recovery of the neutrophils to 10,000
cells/µl. These results suggest that UCN-01 significantly sensitized
normal lymphocytes to relatively modest doses of chemotherapy and may
have affected lymphocyte precursors as well.
|
|
DISCUSSION |
|---|
|
TopABSTRACTINTRODUCTIONCASE REPORTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
In this report, we describe for the first time the clinical effects of UCN-01 and chemotherapy in a patient. A striking result from this case was the achievement of a pathologically complete remission with UCN-01 and EPOCH chemotherapy in a patient with bulky and chemotherapy-resistant lymphoma. Of significance, the patient had previously failed to enter remission after high-dose chemotherapy, which included the same agents and schedules albeit at significantly higher doses (EPOCH II; 3-fold greater doxorubicin and etoposide, 2.7-fold greater vincristine over 2 cycles, and an additional 8000 mg/m2 cyclophosphamide over 2 cycles). After standard-dose EPOCH, the patient developed prolonged neutropenia and enterocolitis, toxicities which may have been due to his underlying clinical condition and/or enhancement of EPOCH toxicity by UCN-01 (6) .
A potentially significant observation was the effect of EPOCH on the
pharmacokinetics of UCN-01. A seeming disadvantage of UCN-01 is the
high protein binding and prolonged terminal half-life. As such, total
plasma concentrations are a poor measure of free drug, and significant
amounts of UCN-01 may be present for weeks after its administration.
Fig. 1
shows the concentration of UCN-01 in plasma and saliva over time
and demonstrates a transient increase in UCN-01 clearance after the
start of EPOCH. The increased clearance of UCN-01 could be explained by
competitive binding between one or more of the EPOCH drugs and UCN-01
for plasma protein binding sites; in support of this are in
vitro studies showing competitive binding between etoposide and
UCN-01 (our unpublished observations). Less likely, UCN-01 may
have been released from dying tissues resulting in a temporary increase
in free drug concentration. However, it is clear from pharmacokinetic
data obtained from other patients that the increased clearance is not
due to plasma concentrations reaching the UCN-01 binding
Km (data not shown). These new data
suggest that the pharmacokinetic profile of UCN-01 may be advantageous,
allowing extended drug exposure and transient increases in free drug
concentrations during chemotherapy administration.
We believe these clinical results indicate that UCN-01 modulated the sensitivity of the patient’s tumor cells to the effects of EPOCH chemotherapy. Indeed, we know of no precedent for any chemotherapy to produce a complete remission in a patient with disease resistant to the same drugs and schedule. Furthermore, although the patient had undergone a histological transformation that arguably might have a different sensitivity pattern (though usually more resistant), both the large and original small cell components of his disease were pathologically eliminated. A potential explanation for this response (which we considered) was a pharmacokinetic interaction between UCN-01 and EPOCH leading to a markedly increased concentration of EPOCH drugs. To assess this possibility, we measured the Css of doxorubicin and etoposide and found them to be within the range of control patients who had received standard dose EPOCH in an earlier study (22) .
To fully characterize the patient’s pathological response, we
performed immunohistochemistry for B and T cell antigens and
immunoglobulin gene rearrangement by PCR. Of interest, there were no
L26+ B cells present in any of the lymph nodes,
liver, or bone marrow specimens obtained from the autopsy, although
scattered CD3+ T cells were observed. Molecular
analysis showed no evidence of the tumor clone in the liver, though a
very faint signal was found in two of six lymph nodes, suggesting only
minimal residual tumor (Fig. 2)
.
These results also suggest that UCN-01 sensitized normal lymphocytes to
the cytotoxic effects of chemotherapy. As shown in Fig. 2
, the normal
background immunoglobulin "ladder" was present in the patient’s
pre-UCN-01/EPOCH biopsy tissues but is absent in all tissues examined
at autopsy, indicating loss of normal B cells. Also striking was the
lack of recovery of the peripheral lymphocyte compartment after EPOCH,
despite a vigorous neutrophil recovery (Fig. 3B)
. This
degree of persistent lymphopenia has not been observed by us in other
patients treated with EPOCH chemotherapy and raises the question of
whether UCN-01 sensitized a lymphocyte precursor compartment to the
effects of chemotherapy. Alternatively, the continued presence of
UCN-01 in the patient may have inhibited lymphocyte recovery, though we
have not observed chronically depressed lymphocyte counts in other
patients treated over prolonged periods with UCN-01 alone. It should be
noted that the immunocompromise from the low lymphocyte counts may have
contributed to the patient’s death from an opportunistic infection.
An important clinical concept to potentially emerge from this case is that of modulating drug resistance by reducing the "threshold" for apoptosis (2) . Experimentally, it is extremely difficult to determine the mechanism of synergy between any two drugs, and this is no less the case with UCN-01 and chemotherapy. Of interest in this regard, experiments by our group in T lymphoblasts suggest that UCN-01 may "independently activate" cdk-1 and cdk-2, leading to abrogation of the G2-M checkpoint (11 , 14) . Additionally, when the Ca-46 Burkitt’s cell line is irradiated in the presence of low nanomolar concentrations of UCN-01, the cells are unable to arrest at G2 and progress to M phase (29 , 30) . The authors noted that the loss of the G2-M fraction temporally corresponds with the appearance of DNA fragmentation and suggested that "the G2-M fraction may be a compartment with greater sensitivity to apoptosis." Others have shown abrogation of the G1 checkpoint by UCN-01, and this too has been associated with a greater sensitivity to induction of apoptosis by DNA-damaging agents (31 , 32) . These results raise the possibility that the inappropriate activation of cdk by UCN-01 may increase the sensitivity to apoptosis and provide a potential mechanism for modulation of the apoptosis sensitivity threshold by UCN-01.
The results raise several intriguing notions regarding the modulation of clinical drug resistance. Perhaps foremost to be addressed is the relationship of apoptosis "threshold" to clinical drug resistance. If, as we hypothesize, this threshold is an important determinant of chemotherapy sensitivity in lymphomas, then strategies to modulate it may lead to major increases in cell kill that are far greater than can be achieved by dose escalation alone, as suggested by the present case report. However, the identification and development of candidate agents require new paradigms. Preclinically, drug screening methods that use conventional cell death end points will likely overlook agents, which could modulate apoptosis thresholds but do not in themselves cause a significant amount of cytotoxicity. If instead such agents were approached as resistance modulators, then (more appropriately) assays would be based on mechanism of action (e.g., involving apoptosis pathways) or on measures of synergy between the candidate agent and a conventional cytotoxic using an apoptosis end point. It is also important to recognize that, because resistance modulators may not necessarily be clinically active when administered alone, their true effectiveness can only be assessed in combination with a cytotoxic.
For those agents that target broadly expressed proteins/pathways, augmentation of normal tissue toxicity, such as effects on normal hematopoietic compartments caused by simultaneously administered cytotoxic drug(s), should not be unexpected and may require specific supportive measures. Theoretically, this may be overcome by the identification of tumor-specific modulating agents. It is intriguing to hypothesize that monoclonal antibodies such as CD20, which activate apoptotic pathways, may functionally modulate the threshold for chemotherapy-induced apoptosis (33) . If, as we hypothesize, the modulation of the apoptosis threshold has the potential to overcome relative drug resistance in hematopoietic neoplasms, the approach could lead to major improvements in clinical outcome.
|
FOOTNOTES |
|---|
1 To whom requests for reprints should be
addressed, at Medicine Branch, National Cancer Institute, Building 10,
Room 12N-226, 9000 Rockville Pike, Bethesda, MD 20892. 
2 The abbreviations used are: UCN-01,
7-hydroxystaurosporine, NSC 638850; cdk, cyclin-dependent kinase;
EPOCH, etoposide, prednisone, vincristine, cyclophosphamide,
doxorubicin; CT, computerized tomography; G-CSF, granulocyte
colony-stimulating factor; LDH, lactate dehydrogenase; HPLC,
high-performance liquid chromatography; Css, steady-state
concentration; IgH, immunoglobulin heavy chain.
Received 8/ 9/99; revised 11/ 2/99; accepted 11/ 2/99.
|
REFERENCES |
|---|
|
TopABSTRACTINTRODUCTIONCASE REPORTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
chain gene. Diagn. Mol. Pathol., 3: 173-178, 1992.
This article has been cited by other articles:
|
|
 |
|
  Y. Dai, M. Rahmani, X.-Y. Pei, P. Khanna, S. I. Han, C. Mitchell, P. Dent, and S. Grant Farnesyltransferase inhibitors interact synergistically with the Chk1 inhibitor UCN-01 to induce apoptosis in human leukemia cells through interruption of both Akt and MEK/ERK pathways and activation of SEK1/JNK Blood, February 15, 2005; 105(4): 1706 - 1716. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Rahmani, C. Yu, Y. Dai, E. Reese, W. Ahmed, P. Dent, and S. Grant Coadministration of the Heat Shock Protein 90 Antagonist 17-Allylamino- 17-demethoxygeldanamycin with Suberoylanilide Hydroxamic Acid or Sodium Butyrate Synergistically Induces Apoptosis in Human Leukemia Cells Cancer Res., December 1, 2003; 63(23): 8420 - 8427. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Patel, T. Lahusen, C. Leethanakul, T. Igishi, M. Kremer, L. Quintanilla-Martinez, J. F. Ensley, E. A. Sausville, J. S. Gutkind, and A. M. Senderowicz Antitumor Activity of UCN-01 in Carcinomas of the Head and Neck Is Associated with Altered Expression of Cyclin D3 and p27KIP1 Clin. Cancer Res., November 1, 2002; 8(11): 3549 - 3560. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Dai, T. H. Landowski, S. T. Rosen, P. Dent, and S. Grant Combined treatment with the checkpoint abrogator UCN-01 and MEK1/2 inhibitors potently induces apoptosis in drug-sensitive and -resistant myeloma cells through an IL-6-independent mechanism Blood, October 16, 2002; 100(9): 3333 - 3343. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. A. Elsayed and E. A. Sausville Selected Novel Anticancer Treatments Targeting Cell Signaling Proteins Oncologist, December 1, 2001; 6(6): 517 - 537. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Fojo Cancer, DNA Repair Mechanisms, and Resistance to Chemotherapy J Natl Cancer Inst, October 3, 2001; 93(19): 1434 - 1436. [Full Text] [PDF]
|
|
|
|
|
|
Y. Dai, C. Yu, V. Singh, L. Tang, Z. Wang, R. McInistry, P. Dent, and S. Grant Pharmacological Inhibitors of the Mitogen-activated Protein Kinase (MAPK) Kinase/MAPK Cascade Interact Synergistically with UCN-01 to Induce Mitochondrial Dysfunction and Apoptosis in Human Leukemia Cells Cancer Res., July 1, 2001; 61(13): 5106 - 5115. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Wieder, F. Essmann, A. Prokop, K. Schmelz, K. Schulze-Osthoff, R. Beyaert, B. Dorken, and P. T. Daniel Activation of caspase-8 in drug-induced apoptosis of B-lymphoid cells is independent of CD95/Fas receptor-ligand interaction and occurs downstream of caspase-3 Blood, March 1, 2001; 97(5): 1378 - 1387. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Harvey, R. Decker, Y. Dai, G. Schaefer, L. Tang, L. Kramer, P. Dent, and S. Grant Interactions between 2-Fluoroadenine 9-{beta}-D-Arabinofuranoside and the Kinase Inhibitor UCN-01 in Human Leukemia and Lymphoma Cells Clin. Cancer Res., February 1, 2001; 7(2): 320 - 330. [Abstract] [Full Text]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
). UCN-01 was slowly eliminated from the plasma at a
constant rate (T1/2 > 1000 h) after its
administration. The UCN-01 concentration acutely declined by 28% on
day 3 and by 78% on day 13 after EPOCH began and thereafter returned
to the pre-EPOCH elimination rate. Salivary concentrations were 22
ng/ml on day 3 of EPOCH.
),
neutrophil (
), and lymphocyte (
) recovery during cycles of
high-dose EPOCH II chemotherapy showing lymphocyte recovery to near
baseline values after each cycle. B, Dynamics of WBC
recovery after UCN-01 and EPOCH therapies. UCN-01 had no effect on WBC
or lymphocyte numbers. After EPOCH, neutrophils rapidly declined but
recovered to 10,000 cells/µl by day 23, whereas the lymphocytes
failed to recover after a nadir of 50 cells/µl.