Download Phase I Study of Tricyclic Nucleoside Phosphate Using a Five

[CANCER RESEARCH 44, 3608-3612,
August 1984)
Phase I Study of Tricyclic Nucleoside Phosphate Using a Five-Day
Continuous Infusion Schedule1
Lynn G. Feun,2 Niramol Savaraj, Gerald P. Bodey, Katherine Lu, Boh Seng Yap, Jaffer A. Ajani,
M. Andrew Burgess, Robert S. Benjamin, Eugene McKelvey, and Irwin Krakoff
Division of Medicine, The University of Texas System Cancer Center, M. D. Anderson Hospital and Tumor Institute, Houston, Texas 77030
ABSTRACT
A Phase I trial of tricyclic nucleoside phosphate (1,4,5,6,8pentaazaacenaphthylene-3-amino-l
,5-dihydro-5-methyl-1 -0-o-ribofuranosyl 5'-phosphate ester; NSC 280594) was conducted
cally dephosphorylated to permit entry into cells, where it is then
rephosphorylated by adenosine kinase (1, 8). Intracellular for
mation of TCN-P appears to be required for cytotoxic activity
(16). TCN-P has demonstrated antitumor activity against L1210
leukemia (15), P388 lymphocytic leukemia, murine CD8F, mam
using a 5-day continuous infusion schedule. Thirty-seven pa
mary carcinoma, and human MX-1 mammary tumor xenograft
tients with advanced cancer were entered on the study, of whom
(2). In the 6-day subrenal capsule assay against surgical implants
33 patients were évaluablefor response and toxicity. Dose levels
of human tumors, TCN-P was the most active single drug of the
ranged from 10 mg/sq m/day x 5 days to 40 mg/sq m/day x 5 9 drugs tested against cervical and ovarian tumors (3).
days. Initially, courses were repeated every 3 to 4 weeks. As
Preclinical toxicology studies were conducted in mice and
cumulative toxicity became manifested, the interval between
dogs. Toxic effects included anorexia, yellow sclera (jaundice),
courses was changed to every 6 weeks. Major toxicities included
prostration, ataxia, emesis, diarrhea, and melena. Hepatic, renal,
hyperglycemia, hepatotoxicity, and thrombocytopenia. Patients
and testicular toxicity as well as myelosuppression were noted.
with a prior history of diabetes mellitus, extensive radiation
In i.p. implanted L1210 leukemia, TCN-P was more effective
therapy, or significant liver métastases were prone to severe
following daily administration for 5 days compared to single bolus
toxicity. Other toxicities noted were nausea and vomiting, ab
doses (2). Although TCN is not very water soluble, TCN-P is
dominal discomfort, anemia, and reduction in serum calcium,
water soluble and is suited for i.v. administration. Since it is
phosphorus, and albumin levels. Rare side effects included hy- possible that TCN-P may be converted rapidly to TCN in the
pertriglyceridemia, hyperamylasemia, diarrhea, and stomatitis.
blood, it seemed reasonable to administer TCN-P by continuous
Antitumor activity observed include improvement in s.c. métas infusion in order to avoid high peak serum concentrations. For
tases in a patient with papillary thyroid carcinoma, stabilization
these reasons, a Phase I study of TCN-P was conducted using
of disease in a patient with mesothelioma, and mixed responses
a 5-day continuous infusion schedule.
in three patients (colon cancer, sarcoma, and tonsillar squamous
cell cancer). Recommended schedule for Phase II studies is 20
MATERIALS AND METHODS
mg/sq m/day for 5 days every 6 weeks.
INTRODUCTION
In 1971, in the course of a study of nucleosides of 7-deazapurines, Schrämand Townsend (12) synthesized a new TCN3
(NSC-154020). TCN appears to enter cells by a nucleoside
transport system (7, 13). The drug is then phosphorylated by
adenosine kinase to TCN-5'-monophosphate
(TCN-P; NSC
280594), which is the more soluble phosphate ester of TCN (1,
8).
The exact mechanism of action of TCN-P is not clear. In
cultured L1210 leukemia cells, the drug inhibited synthesis of
DNA, RNA, and protein, and also reduced ribonucleotide pools
(10). In cultured Chinese hamster ovary cells in vitro, TCN-P
inhibited thymidine and leucine incorporation. Studies with L1210
cells suggest the cytotoxic action of TCN-P may involve inhibition
of DNA synthesis and selective toxicity to S-phase cells (10).
TCN-P is not incorporated into polynucleotides or phosphoryla
ted beyond the monophosphate form (14). TCN-P is enzymati' Supported by National Cancer Institute Contract (Grant 1-CM-27550).
*To whom requests for reprints should be addressed, at The University of
Texas System Cancer Center, M. D. Anderson Hospital and Tumor Institute at
Houston, 6723 Bertner, Houston, TX 77030.
3The abbreviations used are: TCN, tricyclic nucleoside; SGOT, serum glutamic
oxaloacetic acid transaminase; TCN-P, tricyclic nucleoside phosphate (1,4,5,6,8pentaazaacenaphthylene,3-amino,1,5-dihydro-5-methyl-1-/J-D-ribofuranosyl-5'phosphate ester).
Received February 13, 1984; accepted April 26, 1984.
3608
Patients with histological proof of cancer who were not candidates for
established regimens or protocol treatments of higher efficacy or priority
were entered in the study. Patient eligibility requirements included a
performance status of 3 or better (Zubrod scale), a life expectancy of at
least 8 weeks, age of >15 years old, absence of all previous chemo
therapy or radiotherapy for the 3 weeks prior to entering the study (6
weeks for nitrosoureas or mitomycin), and recovery from toxic effects of
any previous therapy, adequate bone marrow function (defined as a
peripheral absolute granulocyte count of >2,000/cu mm and platelet
count of >100,000/cu mm), adequate liver function (serum bilirubin, <2.0
mg/100 ml), and adequate renal function (serum creatinine, <2.5 mg/
100 ml). While measurable lesions were desirable, during this Phase I
study, patients could be entered who had no measurable lesions. All
patients signed an informed consent prior to start of treatment to indicate
that they were aware of the investigational nature of the study.
Pretreatment evaluation included a complete history and physical
examination including documentation of all measurable disease as well
as signs and symptoms. Laboratory studies included a complete blood
count, differential, platelet count, prothrombin time, urinalysis, serum
electrolytes, and a biochemical profile (including blood-urea-nitrogen,
creatinine, SGOT, lactate dehydrogenase, total bilirubin, alkaline phosphatase, calcium, phosphorus, total protein, albumin, and glucose). In
addition, for patients treated at the highest dose levels, base-line insulin
and fasting blood glucose levels were measured. Serum testosterone
and luteinizing hormone levels were performed in all male patients prior
to start of treatment and were repeated monthly while on treatment. An
electrocardiogram and chest roentgenogram were required for each
patient.
CANCER
RESEARCH
VOL. 44
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Phase l Study of Tricyclic Nucleoside Phosphate
TCN-P was obtained from the Division of Cancer Treatment, National
Cancer Institute. The drug was supplied in lyophilized vials containing 50
mg. Prior to use, the drug was reconstituted with 2.5 ml of sterile water
for a concentration of 20 mg/ml/vial with a pH of 6.0 to 7.5. Unpublished
data from our laboratory demonstrated that TCN-P is stable in 0.9%
NaCI solution (saline) for 24 hr. Therefore, the drug was further diluted
with 500 ml of 0.9% saline and infused continuously over 12 hr twice
daily for 5 days. Patients were observed for at least 3 weeks from the
start of therapy before another course was administered.
The initial dose level was 10 mg/sq m daily for 5 days. This dose level
represented less than one-tenth of the 10% lethal dose in mice (300 mg/
sq m). At least 3 patients were treated at each dose level and observed
for 3 weeks prior to starting additional patients at the next higher dose
level. Patients who had no toxicity from their first course of therapy were
eligible to receive a second course of the drug at a higher dose level.
All patients were hospitalized to receive the drug. Evaluation during
study included weekly complete blood count, differential, platelet count,
and biochemical profile. Tumor measurements were recorded every 3
weeks when measurable disease was present.
Initially, treatment was continued every 3 to 4 weeks in the absence
of dose-limiting toxicity or progressive disease. As cumulative toxicity
became manifested during treatment, the interval between courses was
lengthened to 6 weeks.
first 2 weeks of the study. One patient with breast cancer
developed rapidly progressive brain métastases.Another patient
with colon cancer died of perforation of viscus. Two patients
(osteogenic sarcoma of the mandible and metastatic neuroblas
toma) died of nonneutropenic sepsis. Thirty-three évaluablepa
tients received 53 courses of TCN-P. Their patient characteristics
are outlined in Table 1. The number of patients treated at the
respective dose levels is shown in Table 2.
Hematological toxicity appeared to be related to dose and
prior treatment with TCN-P (Table 3). At dose levels less than
40 mg/sq m/day x 5 days, myelosuppression was uncommon.
Patients receiving 40 mg/sq m/day for 5 days as their initial
course of TCN-P also usually did not experience myelosuppres
sion. Patients who received prior courses of TCN-P at 3 to 6
weeks before receiving TCN-P at 40 mg/sq m/day for 5 days
developed severe and prolonged myelosuppression, particularly
thrombocytopenia. Cumulative leukopenia and granulocytopenia
also occurred in these patients. Significant thrombocytopenia
(platelet count, <50,000/cu mm) occurred after a single course
of TCN-P (40 mg/sq m/day for 5 days) in patients with extensive
prior radiation therapy and in patients with extensive liver métas
tases.
Anemia, defined as a drop in hemoglobin more than 1 g/dl,
RESULTS
occurred, particularly at dose levels of 40 mg/sq m/day for 5
Thirty-seven patients were entered into the study. Four pa
days. In 6 patients, there was a decrease in hemoglobin during
tients were considered inevaluable due to early death within the
drug administration. This transient anemia occurred on Days 2
to 7 and was not associated with any symptoms. No elevation
Table 1
of serum láclate dehydrogenase or bilirubin occurred during this
Patients' characteristics
time, and there were no signs of overt hemolysis. The hemoglo
(24-77)18:15132017161054311
(range)Sex
Median age
bin returned to base line in most patients by 1 to 3 weeks. In
(M:F)Prior
several patients, anemia occurred in association with an elevation
therapyChemotherapyRadiotherapy
of the prothrombin time compatible with progressive liver dys
chemotherapyPerformance
+
function or disseminated intravascular coagulation. In these pa
statusOto12DiagnosisColonSarcomaMelanomaLung
tients, the fibrinogen levels dropped below normal with simulta
neous appearance of fibrin split products in the blood. A Coombs
test was performed when clinically indicated. One patient had a
positive Coombs test.
Hyperglycemia was another major toxic effect of TCN-P (Table
(adenocarcinoma)Other
4).
Twenty-seven patients had some elevation of blood glucose
tumors (1 each)57
scheduleDose
(mg/sq m/
day fordays)1020
5
30
40Total
Table 2
Dose
no. of
patients4
3
16
18Total
toxicityNo
courses5
3
2421No.
of patients
treated at initial
dose4
116
12
Tabte3
Hematological
of
lowest re
(mg/sq
m/day for évaluablecorded count x 103/
mm5.0
cu
5 days10 courses4
(4.3-6.9)
3.4 (2.8-5.7)
20
3
5.3(1.2-232)6.0
304040No. 24108WBCMedian
treatmentPrior
prior TCN-P
TCN-P treatmentDose
while on therapy. Hyperglycemia was observed on a median Day
19 after start of therapy (range, 4 to 42 days). Three patients
had a prior history of diabetes mellitus, and 5 additional patients
had mildly elevated base-line blood glucose (ranges, 122 to 130
mg/100 ml). One patient whose diabetes was previously con
trolled with insulin developed progressive hyperglycemia (blood
glucose, 450 to 500 mg/100 ml) while on TCN-P therapy. One
patient developed reversible hyperglycemia while on hyperalimentation. Eighteen patients had presumed drug-related hyper-
lowest re
corded count x 103/
day5
mm3.9
cu
(3.5-5.4)
2.2(1.8-3.8)
11
3.6(0.94-13.9)5.3
131516GranulocytesMedian
(4.5-9.8)2.8(1.3-9.4)Median
(3.2-9.2)1
lowest re
corded count x 103/
mm161
cu
day5
(76-296)
163(58-289)
11
150(29-416)154
131516PlateletsMedian
Day5
5
272126
(6-260)20(10-200)Median
.4 (0.7-6.4)Median
AUGUST 1984
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3609
L. G. Feun et al.
glycemia (median blood glucose, 145 mg/100 ml; range, 125 to
293 mg/100 ml). Among these 18 patients, the blood glucose
returned to normal in 10 patients by median Day 32 (range, 15
to 50 days). Hyperglycemia occurred more frequently at higher
dose levels (greater than 20 mg/sq m/day for 5 days) of TCN-P.
As hyperglycemia became an evident toxicity of TCN-P therapy,
serum insulin levels were performed in patients receiving dose
levels greater than 20 mg/sq m/day for 5 days. In general, serum
insulin values were inappropriately low for the corresponding
blood glucose levels, although 2 patients did have elevated
serum insulin levels after TCN-P. Autopsy examination in 9
patients failed to reveal any gross or microscopic abnormality in
the pancreas.
Hypocalcemia, hypophosphatemia, and hypoalbuminemia oc
curred in several patients (Table 5). In general, the serum calcium
levels corrected for the serum albumin values were borderline
low to low normal. No patient had any symptoms or signs of
hypocalcemia such as tetany. Twenty-four-hr urine collections
for calcium, phosphorus, and albumin were performed in most
patients during the study and were not significantly changed.
Serum parathormone levels were performed serially in 8 patients
and became slightly elevated in 2 patients. Serial serum testos
terone and luteinizing hormone levels were performed in 7 male
patients. While there was no change in the luteinizing hormone
levels in any patient, 3 patients developed below-normal testos
terone levels (0.27 to 0.34 ng/îQQml; normal range, 0.4 to 1.2
Mg/100 ml) while receiving TCN-P. One patient complained of
impotence.
Hepatic toxicity appeared as another major toxic effect of
TCN-P (Table 6), and was manifested by hyperbilirubinemia,
serum transaminase elevation, and a prolongation of the prothrombin time. Hyperbilirubinemia developed in 14 patients, of
whom 4 had progressive massive liver métastases, and 2 had
sepsis with hypotension. In addition, one patient with stomach
cancer had common bile duct obstruction by tumor in the porta
hepatis discovered at autopsy, but not documented by antemor-
which was persistent and irreversible in 6 patients. Hyperbiliru
binemia occurred at dose levels greater than 20 mg/sq m/day
for 5 days and most commonly after the second or third course,
suggesting cumulative hepatic toxicity. In these patients, the
median serum bilirubin level was 3.4 mg/100 ml (range, 1.2 to
12 mg/100 ml). Serum transaminases were also elevated with a
median SCOT of 116 milliunits/ml (range, 50 to >300 milliunits/
ml). Seven patients had prolongation of the prothrombin time
while receiving TCN-P. In 5 of these patients, there was also
elevation of the partial thromboplastin time with decreased serum
fibrinogen levels and platelet counts and increased fibrin split
products, compatible with hepatic dysfunction and/or dissemi
nated intravascular coagulation. Bone marrow examination re
vealed normal megakaryocytes with or without tumor cells pres
ent in the 4 patients studied. Liver biopsies were performed
antemortem in 2 patients, and autopsied liver specimens were
available in 9 patients. In those patients with clinical hepatic
toxicity, histological examination revealed cholestasis and fatty
metamorphosis.
Serum triglycéride levels were performed in 4 patients. In 3
patients, the serum triglycérides were elevated. In 1 of the 3
patients, serum triglycérideswere markedly elevated and asso
ciated with fatty liver.
Other toxicities observed with TCN-P are shown in Table 5.
Mild to moderate nausea and vomiting occurred in a minority of
patients, usually at the end of a treatment course or 1 to 2
weeks afterwards. The nausea subsided after several weeks in
most patients. This did not appear to correlate with hepatic
toxicity. A vague abdominal pain occurred in several patients,
most commonly at dose levels greater than 20 mg/sq m/day for
5 days. The pain was typically right-sided or epigastric in location,
described as an aching or burning sensation, and lasted from
several days to 2 to 3 weeks. It was usually controlled by p.o.
pain medication or cimetidine. Two patients had transient, mild
Tablee
Défaiteof hepatic toxicity
tem computer tomography and ultrasound abdominal scans.
Seven patients had presumedhyperbilirubinemia,Table
drug-related
1No.
4
DoseDose
of courses with toxicity at
following serum bilirubin levels
Details of hyperglycémie toxicity
of courses
(mg/sqhyperglycemia
with toxicity at following
levels
of éva fi>1
(mg/
20-1 99
luable
sq m/day
mg/100
ml23
for 5days)1020 courses5
30
40No.
3
24
21No.
m/day
for
days)mg/1 >300-499
>500
00 ml mg/100 ml (mg/100 ml)
of
5-10
évalua
1.2-5(mg/
mg/
ble
SGOT22(2)a
100ml
courses5 100ml)
>10
mg/
100ml
Elevated
>rothrombin time
and/or dissireminated
itravascular coagula
tion, hemolysis11(1)
1Q20
3
1(1)
5(4)
24
5(4))ers
6(3)
2
3(1)
9(6)»rotonged
21f
.Nlim(Tables
in parentheses, patients felt to have drug-related toxicity.
30
403
13
9>200-299
3
1
2
Other toxicityNo.
coursesDose(mg/sqm/day
No. of
phosphatriglycer-idemia(>170
bumine
cemia(<8.5mg/100
temia(<2.5mg/100
mia(<3.5
ofévaluable
(>81
g/
for
(>1g/dl)2238Hypera-mylase-mia
IU/liter)11Hypermg/dl)3
100ml)147Anemia
ml)1710Hypoml)236Hypoal
tis11Hypocal
tension1Diarrhea11Stomati
nalpain145Lethargy12Hypo
pain2Abdomi
vomiting2e9Chest
courses532421Nausea,
5 days)10203040No.
3610
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Phase l Study of Tricyclic Nucleoside Phosphate
elevation of serum amylase levels. One patient with adenocarcinoma of the lung developed severe right upper quadrant abdom
inal pain 2 to 3 weeks after receiving a single course of TCN-P
at 40 mg/sq m/day for 5 days. Upper and lower gastrointestinal
X-rays were remarkable. Serum amylase levels were normal.
Endoscopy revealed erosive gastritis. A percutaneous liver bi
opsy demonstrated severe fatty metamorphosis. The abdominal
pain was partially relieved by p.o. narcotics and cimetidine.
Lethargy, diarrhea, and stomatitis were other side effects that
occurred rarely after TCN-P. One patient with hepatoma had
transient, asymptomatic hypotension during administration of
TCN-P. The drug was withheld for several hr during which time
the blood pressure rose to a more adequate level. The adminis
tration of the drug was resumed cautiously with no recurrence
of the hypotension.
The dose schedule of TCN-P was changed from 3- to 4-week
intervals between courses to 6-week intervals as the cumulative
drug toxicity became apparent. Two patients received 2 courses
of TCN-P 40 mg/sq m/day x 5 days at least 6 weeks apart. One
patient with malignant fibrohistiocytoma invading the abdominal
aorta tolerated the first course of TCN-P with mild nausea and
vomiting and hyperglycemia (blood glucose, 165 mg/100 ml).
The lowest recorded platelet count was 150,000/cu mm on Day
24. The second course was complicated by thrombocytopenia
(platelet count, <100,000/cu mm) occurring on Day 13. The nadir
was reached at 15,000/cu mm on Day 25. Hepatic dysfunction
and/or disseminated intravascular coagulation occurred with
serum bilirubin elevated at 1.8 mg/100 ml, SCOT at 107 milliunits/ml, and prolongation of the prothrombin time to 14.4 sec.
Blood fibrinogen level dropped from 330 mg/100 ml on Day 16
to 255 mg/100 ml on Day 22, while fibrin split products rose
from 60 /<g on Day 16 to 240 /¿g
on Day 22. Blood glucose was
161 mg/100 ml on Day 20 and then decreased to 110 mg/100
ml on Day 25. The patient became suddenly hypertensive on Day
26 and expired. Permission for postmortem examination was not
granted. The second patient was a 60-year-old man with unclas
sified sarcoma involving the soft tissues, bone, and lung. The
first course of TCN-P was associated with moderate nausea and
vomiting and vague abdominal pain. The second course was
started 7 weeks later. Moderate nausea and vomiting were
encountered, but there was no significant hematological or bio
chemical toxicity noted. The patient expired on Day 36 of the
second course due to progression of his tumor.
Subsequently, 4 patients received TCN-P at 30 mg/sq m/day
x 5 days every 6 weeks for 2 courses. Mildly reversible hyper
glycemia (blood glucose, <200 mg/100 ml) occurred in 3 patients
after the first course. Also noted in one patient were mild nausea
and vomiting and elevation of alkaline phosphatase (127 milliunits/ml). After the second course of TCN-P, mild hyperglycemia
occurred in 2 patients and was reversible in one patient. One
patient had thrombocytopenia (platelet count, 94,000/cu mm) on
Day 28 of the second course. Two patients developed moderate
nausea and vomiting and abdominal pain lasting 1 to 2 weeks.
One of these patients had elevation of serum amylase to 145
units on Day 39 which dropped to 90 units by Day 41. This
patient also had mild elevation of SGOT on Day 39. No other
significant hematological or biochemical abnormalities were
noted.
Suggestion of drug antitumor activity was noted in several
patients. A patient with papillary thyroid carcinoma had disap
pearance of s.c. métastasesand stability of pulmonary métas
tases for at least 4 weeks. One patient with mesothelioma had
stable disease for 2.5 months. Three patients had mixed re
sponses including one patient with unclassified sarcoma and
multiple s.c. métastases,a second patient with colon carcinoma
with hepatic and peritoneal métastases,and a third patient with
squamous cell carcinoma of the tonsil with cervical métastases.
No patient had a complete or partial response (>50% reduction)
to TCN-P.
DISCUSSION
This Phase I trial of TCN-P using a 5-day continuous infusion
schedule was based on preclinical studies which showed that
daily administration of the drug for 5 days was more effective
than single bolus doses. TCN-P is water-soluble, while TCN is
not. Since it is possible that TCN-P may be converted to TCN in
the blood, a continuous infusion schedule of TCN-P was used
to avoid high peak serum level. In fact, preliminary pharmacologi
cal studies suggest that TCN-P is dephosphorylated to TCN in
the blood and enters RBC as TCN where the drug is rephosphorylated to TCN-P (5).
Hepatic toxicity, hyperglycemia, and thrombocytopenia were
the major toxic effects of TCN-P observed in this study. Similar
toxic effects were observed when TCN-P was infused over 15
min once every 3 weeks (6). In the Phase I study using the latter
schedule, hyperglycemia and elevation of hepatocellular en
zymes were observed beginning at a dose of 250 mg/sq m; 2
patients were reported to have developed irreversible liver dam
age at a dose of 350 mg/sq m. Severe thrombocytopenia (platelet
counts, <25,000/cu mm) was observed in 4 patients. Data were
not available to indicate whether the abnormalities observed
were cumulative or dose limiting.
In the study reported here, a single course at dose levels up
to 40 mg/sq m/day x 5 days as a continuous infusion was
generally tolerated, except in patients with hepatic dysfunction,
diabetes mellitus, or extensive prior radiation therapy. Patients
with massive liver métastases receiving this dose developed
progressive hepatic dysfunction, manifested as hyperbilirubinemia and elevation of hepatic cellular enzymes. In addition, throm
bocytopenia became severe.
Patients with extensive prior radiation therapy involving major
portions of the bone marrow also developed severe thrombocy
topenia. Hyperglycemia in diabetic patients appeared to be ag
gravated by TCN-P therapy.
As the cumulative toxicity of the drug became manifest, further
patients were started at a lower dose level of 30 mg/sq m/day
for 5 days and courses were repeated every 6 weeks instead of
3 to 4 weeks. Mild, reversible hyperglycemia and nausea and
vomiting occurred. More importantly, 2 patients developed vague
abdominal discomfort after the second course, and one of these
patients had mild elevation of serum amylase. It is not known
whether cumulative toxicity on this dose schedule would have
precluded further courses of TCN-P. Based on the available
data, it would be reasonable to recommend a lower dose level
of 20 mg/sq m/day for 5 days every 6 weeks for initiating Phase
II trials. It is possible that patients who are in better condition
and less heavily treated may tolerate a dose level of 30 mg/sq
m/day for 5 days.
The mechanism of action underlying the major toxic effects of
AUGUST 1984
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3611
L G. Feun et al.
TCN-P is unknown. Drugs such as phenothiazines and androgens may produce similar hepatotoxicity resulting in fatty liver
and cholestasis. Earlier pharmacology studies of TCN in dogs
have demonstrated that the majority of the administered drug
was excreted in the bile (4). In fact, crystallized drug was
detected in the bile ducts. We have compared the pharmacology
of TCN and TCN-P in dogs (11). In 5 hr, 44% of the administered
dose of TCN was found in the bile, none as TCN-P. When TCNP was administered, 20.2% of the drug was detected in the bile
as TCN. Similar studies in rabbits have shown that 30% of the
administered dose of TCN-P was detected in bile as TCN (9). No
crystallized drug could be detected in the bile ducts of patients
on whom liver biopsies or postmortem examinations were per
formed. It is conceivable that TCN crystals would have dissolved
before or during the preparation of slides for histológica! exami
nation. Whether mechanical plugging of the bile ducts or canaliculi by TCN is the actual mechanism of hepatic toxicity is un
known.
Study of the tissue and tumor concentrations of TCN-P and
TCN was accomplished in 4 patients who expired 4 to 6 weeks
after receiving 40 mg/sq m/day for 5 days of TCN-P (17). TCNP and TCN were analyzed by high-performance liquid chromatography. The highest TCN-P concentration was found in the
liver 6.3 ±0.8 ng/g for patients who expired 4 weeks after
therapy. The concentration in the liver was 3.8 »g/g for the
patient who expired 6 weeks after TCN-P. Significant amounts
of TCN-P were found in the pancreas (3.9 ±0.3 ¿¿g/g).
Less than
1 fig/g was found in the heart, lungs, and small intestine. The
highest TCN-P concentrations in the liver and pancreas seemed
to correlate with clinical liver toxicity and hyperglycémie. It is
possible that tissue persistence of TCN-P for 4 to 6 weeks may
result in cumulative toxicity. TCN was detected also in plasma
of all patients treated with TCN-P (5). The highest plasma con
centration of TCN, 0.5 ng/m\, was in 2 patients who developed
severe liver dysfunction after TCN-P. TCN-P was taken up
significantly by RBC and to lesser extent by platelets, but not
WBC. Its t,,, in RBC averaged 28.3 hr, whereas in a patient with
minor hepatic dysfunction, it was 93 hr. Plasma TCN concentra
tions seemed to correlate with drug-related liver toxicity. These
results suggested that plasma TCN and RBC TCN-P levels
should be monitored in patients receiving this drug to avoid
cumulative toxicity (17).
In this study, suggestion of antitumor activity was noted in 5
patients with various tumor types. It is interesting that TCN-P
was either more active or comparable in antitumor activity to
several standard chemotherapeutic agents against surgical explants of human tumors in the 6-day subrenal capsule assay (3).
TCN-P was the most active single agent tested against cervical
and ovarian tumors. Further clinical studies using TCN-P should
probably include patients with gynecological tumors.
Phase II trials using a 5-day continuous infusion of TCN-P
should involve close monitoring of liver and pancreatic function
tests. Patients with a prior history of diabetes mellitus, liver
dysfunction, or massive hepatic métastasesshould be excluded
3612
due to the hyperglycemia and hepatotoxicity of the drug. Patients
with extensive prior radiation therapy may be at risk to develop
significant thrombocytopenia and should probably receive lower
doses of TCN-P or be excluded from this therapy. Further data
will be needed to determine whether monitoring of plasma TCN
and RBC TCN-P levels during therapy (17) will be helpful to avoid
cumulative toxicity.
REFERENCES
1. Bennett, L. L, Jr., Smithers, D., Hill, D. L, Rose, L. M., and Alexander, J. A.
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CANCER
RESEARCH
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VOL. 44
Phase I Study of Tricyclic Nucleoside Phosphate Using a
Five-Day Continuous Infusion Schedule
Lynn G. Feun, Niramol Savaraj, Gerald P. Bodey, et al.
Cancer Res 1984;44:3608-3612.
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