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Clinical Trials |
-Difluoromethylornithine-Procarbazine, N-(2-Chloroethyl)-N'-cyclohexyl-N-nitrosurea, Vincristine (DFMO-PCV) Versus PCV for Glioblastoma Multiforme1
Departments of Neuro-Oncology [V. A. L., J. H. U., K. A. J., W. K. A. Y., A. P. K., M. J. G.], Pathology, Section of Neuropathology [J. M. B.], and Biomathematics [K. R. H.], University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030; Marshfield Clinic, Marshfield, Wisconsin 54449-5777 [A. C.]; Metro-Minnesota, Community Cancer Oncology Program, St. Louis Park, Minnesota 55416 [P. J. F.]; and University of California, San Francisco, Neuro-Oncology Services, San Francisco, California 94143-0372 [M. D. P., S. M. C.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONPATIENTS AND METHODSDetermination of ResponseCriteria for Removing Patients...StatisticsRESULTSDISCUSSIONREFERENCES |
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-difluoromethylornithine (eflornithine), an
inhibitor of ornithine decarboxylase, which has shown encouraging
results in the setting of recurrent glioma patients, to a
nitrosourea-based therapy (PCV) would constitute a more effective
adjuvant therapy in the treatment of glioblastoma multiforme patients
in the post-radiation therapy setting.
Following conventional radiation therapy, 272 glioblastoma (GBM)
patients were randomized to receive either
-difluoromethylornithine-PCV (DFMO-PCV; 134 patients) or PCV
alone (138 patients), with survival and time to tumor progression being
the primary endpoints. The starting dosage of DFMO was 3.0
g/m2 p.o. q8h for 14 days before and after treatment with
N-(2-chloroethyl)-N-cyclohexyl-N-nitrosurea;
PCV was administered as previously described1. Clinical and
radiological (Gadolinium-enhanced MRI) follow-ups were nominally at the
end of each 6 or 8 week cycle (PCV at 6 weeks; DFMO-PCV at 8 weeks).
Laboratory evaluations for hematologic and other adverse effects were
at 2 week intervals.
There was no difference in median survival or median time-to-tumor progression between the two treatment groups, as measured from day of commencement of postradiotherapy chemotherapy [MS (months): DFMO-PCV, 10.5; PCV, 11.1; MTP (months): DFMO-PCV, 4.6; PCV, 4.4]. Overall survival, as measured from time of tumor diagnosis at first surgery, was 13.3 and 14.2 months at the median and 6.2 and 8.7% at 5 years, respectively, for the DFMO-PCV and PCV arms. The treatment effect was unchanged after adjustment for age, performance status (KPS), extent of surgery, and other factors using the multivariate Cox proportional hazard model. Adverse effects associated with DFMO consisted of gastrointestinal (diarrhea nausea/vomiting), cytopenias, and minimal ototoxicity (limited to tinnitus) at the dose range tested.
The addition of DFMO to the nitrosourea-based PCV regimen in this phase III study demonstrated no additional benefit in glioblastoma patients, underscoring the resistance of glioblastoma multiforme tumors to alkylating agents. For patients with anaplastic (intermediate grade) gliomas, in which the previously demonstrated benefit of post-radiation chemotherapy is more substantial, the evaluation of DFMO-PCV vs. PCV is still ongoing and hopefully will yield more encouraging results.
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSDetermination of ResponseCriteria for Removing Patients...StatisticsRESULTSDISCUSSIONREFERENCES |
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As single agents, polyamine inhibitors such as DFMO have only infrequently shown activity against human tumors in a clinical setting. In combination with other drugs that interfere with polyamine metabolism, such as methylglyoxal bis-guanylhydrazone (6) , or drugs that interfere with DNA function (7, 8, 9, 10) , evidence implicates a synergistic interaction of DFMO against tumor cells.
With respect to malignant gliomas, the combination of DFMO with the BCNU nitrosourea has shown consistent potentiation of 9L cell kill and increased survival in rats with intracerebral 9L tumors (2 , 6, 7, 8, 9) . In the patient setting, Prados et al. (11) had demonstrated encouraging results in a Phase I-II study of DFMO-BCNU in the treatment of patients with recurrent gliomas. Of the 21 evaluable supratentorial anaplastic glioma patients, 2 (10%) experienced a PR and 10 (48%) had disease stabilization with therapy. The MS for these 12 patients was 119 weeks (measured from the initiation of chemotherapy), which was far superior to the MS of 56 weeks for the entire anaplastic glioma group of 21 patients.
The encouraging results with the DFMO-BCNU combination in the setting of recurrent anaplastic gliomas formed the basis for the current Phase III study, in which patients with newly diagnosed high-grade malignant gliomas received DFMO together with a nitrosourea combination in the postradiotherapy setting. Because the three-drug regimen PCV has been demonstrated to be more effective against anaplastic astrocytomas than the nitrosourea BCNU alone (12) , the study randomized between DFMO-PCV versus PCV alone for two histological strata: anaplastic astrocytoma and GBM. This report presents data related only to the GBM stratum of the randomized study.
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PATIENTS AND METHODS |
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16 years of age;
(e) KPS, 
70 with a life expectancy of at least 8 weeks;
(f) normal liver function (serum glutamic pyruvic
transaminase, alkaline phosphatase levels 2 times normal
values and total bilirubin 1.5 mg/dl); (g) normal hemogram
including absolute neutrophil count of 1500/mm3
and platelets, 125,000/mm3
; and (h)
lack of active infection, pregnancy (adequate contraception required),
any disease that would obscure toxicity or dangerously alter drug
metabolism, and serious intercurrent illness. All of the patients
signed an Institutional Review Board-approved informed consent form.
The MDACC served as the central registration site. All of the
patients’ scans and pathology slides were reviewed at MDACC before
registration and randomization via a computer-generated randomization
program. Patients were stratified only by histology (GBM
versus anaplastic glioma). The two strata had different
accrual goals and they constitute two separate studies. For GBM, the
trial was powered to detect a MS of 75 weeks as different from 50 weeks
based on a 1-sided log-rank test with = 5% and ß =
20%. The target sample size in the original protocol for the GBM
patient group was 237, based on an accrual rate of 1.5 per week and a
26-week post accrual follow-up period. The final accrual for the GBM
study presented in this report was 272, because the target size was
increased because of slow accrual.
Treatment
Eflornithine5
was
prepared as a premixed 500-ml solution containing DFMO at a
concentration of 200 mg/ml in 5% ethanol. The solution was
stored in a cool environment (<85°C) out of direct
light, under which conditions it is stable. The drug was made available
by the Division of Cancer Treatment, NCI (NSC 337250) through a
gift from Merrell Dow Pharmaceuticals, Inc.
Before initiating the randomized study, we conducted a Phase I evaluation of escalating DFMO doses of 2, 2.5, and 3 g/m2 /day based on the DFMO dosage used in the BCNU-DFMO and DFMO studies (11 , 13) . There were four to seven patients in each treatment cohort. Dose-limiting diarrhea and combined myelotoxicity with PCV determined the dosage used in this study. Ototoxicity was not observed to be a dose-limiting toxicity in our Phase I study. After randomization, patients received one of the two following treatment schedules:
Arm A: DFMO (eflornithine) in combination with PCV DFMO, 3.0 g/m2 p.o. every 8 h, days 1–14 PCV beginning day 15 CCNU, 110 mg/m2 p.o., day 15 Procarbazine, 60 mg/m2 /day p.o., days 22–35 Vincristine, 1.4 mg/m2 i.v. (max, 2.0 mg), day 22 and day 43 DFMO, 3.0 g/m2 p.o. every 8 h, days 29–42 The cycle was repeated at 8-week intervals, for a total of seven cycles. Arm B: PCV alone (1 ) CCNU, 110 mg/m2 p.o., day 1 Procarcazine, 60 mg/m2 p.o./day, days 8–21 Vincristine, 1.4 mg/m2 i.v. (max, 2.0 mg), days 8 and 29 The cycle was repeated at 6-week intervals, for a total of seven cycles.
Evaluation for Toxicity and Dose Adjustments
Pretreatment Evaluation.
Pretreatment evaluation consisted of a complete medical history,
Karnofsky performance status, and general physical and neurological
examinations. Contrast-enhanced MRI and/or CT scan of brain
within 2 weeks prior to treatment (patients from Centers outside the
MDACC had their scans reviewed at MDACC before study entry). Blood
tests (complete blood count, differential, platelet count, creatinine,
bilirubin, alkaline phosphatase, and alanine aminotransferase)
the results of which conformed to entry guidelines (see "Patient
Eligibility") were obtained within 1 week prior to study entry.
Evaluation during Study.
Evaluation during study consisted of the same clinical, radiological,
and laboratory exams as those listed for "Pretreatment Evaluation."
A complete neurological examination and neuro-imaging
(contrast-enhanced MRI or CT scan) were performed before each cycle of
chemotherapy. Complete blood count, differential, and platelet counts
were obtained every 2 weeks during PCV and PCV-DFMO courses. If the
absolute neutrophil count fell below 750/mm3
and/or platelets fell below 50,000/mm3
, then
counts were obtained more frequently until counts rose above these
levels. Serum creatinine, alkaline phosphatase, bilirubin, and alanine
aminotransferase tests were performed before each cycle of
chemotherapy. All of the toxicities encountered during the study were
graded (0–4) according to the NCI Common Toxicity Criteria and
were recorded before each course of therapy. Dose adjustments for
life-threatening toxicities were to be reported immediately to the
Study Chairman, the Institutional Review Board, and the NCI.
Dose Modification.
Doses of procarbazine and CCNU were modified at the beginning of each
new course according to the grade of absolute neutrophil count
and platelet-nadirs experienced during the previous course:
(a) grade 0, increase by 25%; (b) grades 1 and
2, no change; (c) grade 3, decrease previous dose by 25%;
and (d) grade 4, decrease initial dose by 50%.
Dose modification for DFMO was based on ototoxicity. For ototoxicity greater than grade 2 (tinnitus), the dose was to be decreased 25%; therapy was not to be withheld, inasmuch as ototoxicity was demonstrated earlier to be dose- and schedule-dependent and typically resolved after either a dose reduction or a drug holiday. Audiometric testing was performed at the physician’s discretion for patients who, on history and/or examination, demonstrated evidence of hearing loss.
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Determination of Response |
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A CR was defined as a MRI (or CT) scan with no visible tumor, provided that the patient had had no increase in glucocorticoid dose since the last evaluation period. A PR was defined as less than a CR but greater than a 50% reduction in the product of the two largest tumor diameters, provided that the patient had had no increase in glucocorticoid dose since the last evaluation period. A MR was defined as an unequivocal reduction in tumor size that either was less than a 50% reduction in the product of the two largest diameters or could not be measured. "Stable disease" was defined as <25% change in tumor size (with the patient receiving stable or decreasing doses of glucocorticoids). "Progressive disease" was defined as a >25% increase in tumor size, provided that the dose of glucocorticoids had not been decreased since the last evaluation period; if the glucocorticoid dose was concomitantly decreased, theoretically, the progressive disease designation had to be confirmed at the next evaluation period.
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Criteria for Removing Patients from the Study |
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Statistics |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSDetermination of ResponseCriteria for Removing Patients...StatisticsRESULTSDISCUSSIONREFERENCES |
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RESULTS |
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summarizes patient characteristics in
the two treatment groups. Although randomization yielded a balance with
respect to most patient characteristics, the DFMO-PCV group consisted
of patients with a slightly higher median age (52.7 years compared with
49.6) and a higher proportion of female patients (38 versus
26%) compared with the group that received PCV alone (Table 2)
. The treatment effect was unchanged
after adjustment for these differences using the multivariate Cox
proportional hazard model.
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Toxicity.
In general, both of the treatment arms were well tolerated. Table 3
lists the adverse effects that were
above grade 2. Although DFMO in higher doses has been associated with
sensorineural hearing deficits, no patients in the DFMO-PCV group was
recorded to have experienced ototoxicity worse than grade 2 (defined as
tinnitus). Diarrhea was an adverse effect that was restricted to the
DFMO-PCV group. In one case, the diarrhea was that of grade 4, with
10 stools/day and a need for parenteral support.
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. One patient on the PCV treatment
arm experienced a grade 4 elevation in bilirubin, which resolved within
3 days of onset, and one patient receiving DFMO-PCV experienced
dehydration leading to renal failure.
Response.
Kaplan-Meier analyses demonstrated no difference in survival (Fig. 1)
or progression-free survival (Fig. 2)
between the two treatment groups: MS
with DFMO-PCV treatment, 10.5 months; MS with only PCV treatment, 11.1
months; MTP for the respective groups were 4.6 and 4.4 months.
Univariate hazard ratio for overall survival (DFMO-PCV
versus PCV alone) was 1.0 (95% CI, 0.9–1.1;
P = 0.55), which did not change after adjustment for
covariates. Univariate hazard ratio for progression-free survival was
1.0 (95% CI 0.9, 1.1; P = 0.68), which did not change
after adjustment. Overall survival, as measured from time of tumor
diagnosis at first surgery, was 13.3 and 14.2 months at the median and,
at 5-year, 6.2 and 8.7%, respectively, for the DFMO-PCV and PCV arms.
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For both groups combined (total of 272 patients), 225 progressed (189
while on treatment), and 47 were alive and progression-free after a
median follow-up of 11 months. As shown in Table 2
, a Cox model with
four prognostic factors (age, KPS, extent of resection, side of tumor)
accounted for 30% (value of
R2
) variation in survival.
In each of the two treatment groups, there were 13 responders. The DFMO-PCV group had 2 CR, 5 PR, and 6 MR. The group treated with PCV alone had no CR, but had 6 PR and 7 MR (see "Determination of Response" in "Patients and Methods" section for response criteria). Twenty-three patients were listed as inevaluable (14 in the DFMO-PCV group, 9 in the PCV-alone group), but a review of the data revealed that results were unaffected by their exclusion.
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DISCUSSION |
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We as well as other groups have previously reported extensive in vitro (7 , 9 , 23, 24, 25, 26, 27, 28) and in vivo results from animal studies (8 , 29, 30, 31) that demonstrated the antiglioma effects of DFMO, an irreversible inhibitor of ODC (32) . In addition, these preclinical studies had also shown that DFMO potentiates the cytotoxicity of the nitrosourea BCNU (8 , 28) . As a result, a Phase I-II study was subsequently performed to evaluate DFMO in combination with BCNU in recurrent malignant glioma patients (11) . Whereas the DFMO-BCNU combination demonstrated only minimal activity in patients with recurrent GBM, results with patients with recurrent anaplastic gliomas were more impressive (PR, 10%; stable disease, 48%) with what appeared to be an unexpected cohort of long-term survivors. As such, the data supported a need for a prospective randomized study comparing the DFMO-BCNU versus BCNU alone, at least in the anaplastic glioma population.
Because we had previously shown that the nitrosourea-based combination of PCV to be superior to BCNU alone in patients with anaplastic gliomas (12) , we felt obligated to conduct a Phase III study that randomized patients to receive either DFMO-PCV or PCV alone. In this multi-institutional study, patients afflicted with anaplastic glioma or GBM were accrued and stratified at entry by histology. The current report presents only the data pertinent to the GBM population.
Despite the encouraging preclinical and Phase I-II clinical
studies supporting a synergism between DFMO and a nitrosourea, the
addition of DFMO to PCV provided no significant extension in MS from
postirradiation randomization (10.5 months; Fig. 1
), overall MS from
diagnostic surgery (13.3 months), or progression-free survival (MTP,
4.6 months; Fig. 2
) compared with treatment with PCV alone. As
expected, age and KPS at study entry were identified to be of potential
prognostic significance (Table 2)
. Although overall- and
progression-free survival were unchanged after adjustment for
differences between patient groups, further analysis of the data did
suggest an apparent benefit of DFMO-PCV over PCV in younger patients;
for patients 40 or younger, survival hazard ratio for treatment
with DFMO-PCV versus PCV alone was 0.5 (95% CI, 0.2–1.1;
P = 0.028), whereas for patients 40 or older,
the hazard ratio was 1.3 (95% CI, 0.9–1.7). No explanation or
judgment can be currently drawn from this observation.
Whether a higher dose of DFMO might have produced more encouraging results in this study is moot. Patients with recurrent anaplastic glioma in a short, Phase I study of PCV-DFMO before the randomized study began did not tolerate DFMO at the monotherapy dose of 3.6 g/m2 (13) . However, in contrast, DFMO was administered at a significantly lower dose (2.0 g/m2 per dose) in our previous Phase I-II study assessing the DFMO-BCNU combination, in which the combination was superior in anaplastic glioma patients compared with historical controls treated with BCNU alone (11) . Importantly, whereas the aforementioned studies of DFMO as a monotherapy or in combination with BCNU produced encouraging results, the antitumor activity of DFMO in these previous studies was readily apparent only with patients with anaplastic gliomas.
GBMs are characteristically more resistant to conventional alkylating agents, a property that has been attributed to various genetic aberrations that distinguish GBM tumors from the lower-grade gliomas of the anaplastic or low-grade type (33) . However, whether GBMs are distinct from the lower-grade histologies specifically with respect to their susceptibility to perturbations in polyamine metabolism is not known. In vitro, cell lines derived from human high-grade gliomas as well as rodent glioma and gliosarcomas models are sensitive to DFMO (7 , 9 , 23, 24, 25, 26, 27, 28) , although this sensitivity is not universal among all GBM cell lines (28) . Nonetheless, in vitro studies that specifically compare the relative sensitivities of gliomas of different grades to ODC inhibition are lacking. In contrast, there have been in vivo studies with functional neuro-imaging techniques that indirectly measure ODC activity in patients, but these have not demonstrated any significant difference in the activity of this enzyme as a function of glioma grade (34) .
The lack of an apparent potentiation between DFMO and PCV in the current study with GBM patients raises the question of whether DFMO would be more active if it were administered in combination with another class of drug or treatment modalilty. Compared with the extensive in vitro and preclinical data that supported the combinatory regimen of DFMO and nitrosourea, the data pertaining to DFMO combination with other agents is significantly less. In the rodent model, radiation, when given concurrently with DFMO, led to an additive effect on the reduction polyamime levels, which correlated with an increase in the survival of rats orthotopically implanted with malignant glioma (35) . DFMO in combination with cis-platinum has been mixed. Whereas synergism was observed between DFMO and cis-platinum in a rodent model (36) , another study showed that the DFMO with cis-platinum was actually less cytotoxic than platinum alone (28) . With respect to biological response modifiers, whereas in vitro results demonstrated the DFMO with IFN was additive in terms of antitumor effect (37) , subsequent Phase II evaluation of this combination failed to confirm this result in the patient setting (38) .
In conclusion, we have presented the results of a prospective, randomized Phase III study of 272 patients comparing the DFMO-PCV combination versus PCV alone in patients with GBM in the postradiotherapy setting. We observed no significant advantage of the addition of DFMO to the nitrosourea regimen in terms of the two primary end points, survival and progression-free survival (MTP). Whereas the results of this study of GBM patients are "negative," (i.e., the addition of DFMO to PCU did not improve survival) they underscore the importance of controlled trials in the assessment of cancer therapeutics. Moreover, we are hopeful that the evaluation of DFMO-PCV versus PCV in anaplastic glioma patients may yield encouraging results when it is analyzed in early 2001.
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FOOTNOTES |
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1 Supported in part by NIH Grant CA55261. 
2 To whom requests for reprints should be
addressed, at Department of Neuro-Oncology, The University of Texas
M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 100,
Houston, Texas 77030. Phone: (713) 792-8297; Fax: (713) 794-4999;
E-mail: vlevin{at}mdanderson.org
3 Present address: Department of Neurology, Mayo
Clinic, 200 First Street SW, Rochester, Minnesota 55905.
4 The abbreviations used are: DFMO,
-difluoromethylornithine (eflornithine); CCNU,
N-(2-chloroethyl)-N'-cyclohexyl-N-nitrosurea;
PCV, procarbazine, CCNU,
vincristine; GBM, glioblastoma multiforme; ODC,
ornithine decarboxylase; MTP, median-time(s)-to-tumor progression; MS,
median survival; KPS, Karnofsky performance status; BCNU,
1,3-bis(2-chloroethyl)-1-nitrosurea, MDACC, M. D. Anderson Cancer
Center; CI, confidence interval; MRI, magnetic resonance imaging; CT,
computed tomography; NCI, National Cancer Institute; CR, complete
response; PR, partial response; MR, minor response.
5 Eflornithine,
DL--difluoromethyl-2,5-diaminopentanoic acid
hydrochloride, monohydrate.
Received 3/30/00; revised 7/10/00; accepted 7/13/00.
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REFERENCES |
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-difluoromethyl ornithine in cultured cells. A consequence of the irreversible inhibition of ornithine decarboxylase. Biochem. Biophys. Res. Commun., 81: 58-66, 1978.[CrossRef][Medline]
-difluoromethylornithine, an irreversible inhibitor of ornithine decarboxylase. Life Sci., 26: 181-194, 1980.[CrossRef][Medline]
-difluoromethylornithine, an enzyme-activated irreversible inhibitor of ornithine decarboxylase, on L1210 leukemia in mice. Cancer Res., 38: 3059-3062, 1978. difluoromethyl ornithine. Prostate, 3: 383-389, 1982.[Medline]
-difluoromethylornithine, an ornithine decarboxylase inhibitor. Cancer Res., 41: 2783-2785, 1981.-difluoromethylornithine, an ornithine decarboxylase inhibitor. Cancer Res., 41: 4426-4431, 1981.
-difluoromethylornithine in chloroethylnitrosourea-sensitive and -resistant 9L rat brain tumor cells in vitro. Cancer Res., 43: 3576-3578, 1983.-difluoromethyl ornithine potentiates the cytotoxic effects of 1-ß-D-arabinofuranoxylcytosine in HeLa cells. Biochem. Biophys. Res. Commun., 95: 423-430, 1980.[CrossRef][Medline]
-difluoromethylornithine. Neurosurgery (Baltimore), 24: 806-809, 1989.[Medline]
-difluoromethylornithine-induced polyamine depletion in 9L rat brain tumor cells. Cancer Res., 44: 1819-1822, 1984.-difluoromethylornithine inhibits proliferation and the G1 to S transition. Exp. Cell Res., 131: 209-216, 1981.[CrossRef][Medline]
-difluoromethylornithine (DFMO) enhanced [3H]putrescine uptake on 9L tumor cell growth and colony forming efficiency. Int. J. Radiat. Oncol. Biol. Phys., 25: 639-646, 1993.[Medline]
-difluoromethylornithine on 1,3-bis(2-chloroethyl)-1-nitrosourea and cis-diamminedichloroplatinum(II) cytotoxicity. DNA interstrand cross-linking, and growth in human brain tumor cell lines in vitro. Cancer Res., 50: 2769–2772, 1990.
-difluoromethylornithine in rats and dogs. Cancer Chemother. Pharmacol., 10: 196-199, 1983.[Medline]
-difluoromethylornithine (DFMO) and radiation therapy on a rat glioma model. J. Cancer Res. Clin. Oncol., 118: 171-175, 1992.[CrossRef][Medline]
-Difluoromethylornithine increases the anti-tumor effect of cis-diamminedichloroplatinum in G-XII rat glioma. Neurol. Med.-Chir., 35: 215-220, 1995.
and ß interferon on human glioma cells. J. Neuro-oncol., 5: 323-330, 1987.[CrossRef][Medline]
-2a and eflornithine in patients with recurrent glioma. J. Neuro-oncol., 36: 65-70, 1998.[CrossRef][Medline]
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V. A. Levin, K. R. Hess, A. Choucair, P. J. Flynn, K. A. Jaeckle, A. P. Kyritsis, W. K. A. Yung, M. D. Prados, J. M. Bruner, S. Ictech, et al. Phase III Randomized Study of Postradiotherapy Chemotherapy with Combination {alpha}-Difluoromethylornithine-PCV versus PCV for Anaplastic Gliomas Clin. Cancer Res., March 1, 2003; 9(3): 981 - 990. [Abstract] [Full Text] [PDF]
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S. A. Christopher, P. Diegelman, C. W. Porter, and W. D. Kruger Methylthioadenosine Phosphorylase, a Gene Frequently Codeleted with p16cdkN2a/ARF, Acts as a Tumor Suppressor in a Breast Cancer Cell Line Cancer Res., November 15, 2002; 62(22): 6639 - 6644. [Abstract] [Full Text] [PDF]
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