Apoptotic Mechanisms of Gallium Nitrate: Basic and Clinical Investigations
Apoptotic Mechanisms of Gallium Nitrate: Basic and Clinical Investigations
Gallium, like aluminum, indium,
and thallium, is a naturally
occurring group IIIa
metal. Commercially available for
therapeutic use as the nitrate salt
(Ganite), gallium has an oxidation
state of +3; its electric charge, ion diameter,
coordination number, and
electronic configuration are similar to
those of iron (Fe+++). However, at
neutral pH, gallium does not transition
between divalent and trivalent oxidation
states; therefore, unlike iron, it
does not participate in biologic redox
Gallium is the second metal with
clinical antitumor activity. Interest
in the use of gallium and other metals
as chemotherapeutic agents was
heightened after platinum (a group
VIII metal) was discovered to have
potent antineoplastic activity.[4,5]
Prior to 1970, the use of gallium was
confined mainly to the development
of radiogallium (67Ga) as an imaging
agent for the diagnosis of malignancy.[
4] In 1971, investigators at the
National Cancer Institute studied the
antitumor activity of group IIIa metal
salts-including aluminum, thallium,
indium, and gallium-in vitro and in
animal tumor models. These studies
showed that gallium nitrate had the
highest antitumor activity with moderate
Mechanism of Action in
The mechanisms involved in the
uptake of radiolabeled gallium (67Ga)
by malignant tumors in vivo have
been of interest since its identification
as a tumor-localizing agent. In the circulation,
gallium is bound to the iron
transport protein transferrin, forming
Approximately one-third of circulating
transferrin binds iron, leaving the
remaining two-thirds free to bind gallium.
Transferrin-iron complexes and
transferrin-gallium complexes competitively
bind to transferrin receptors
and are incorporated into cells via
transferrin receptor-mediated endocytosis.[
Known and potential mechanisms
involved in the cytotoxicity of gallium
are illustrated in Figure 1. The primary
mechanisms appear to include interference
with iron utilization, inhibition
of ribonucleotide reductase, and induction
of apoptosis. Gallium may
also have effects on mitochondria.
Other evidence indicates that gallium
blocks the secretion of interleukin-6
in a concentration-dependent manner
in macrophage-like cells. In vitro,
gallium also inhibits tyrosine phosphatase
in lymphoid cell lines; however,
it is not clear how this relates to
its antitumor activity.
Findings from an in vitro study using
HL60 cells suggested that two
mechanisms are involved in the cellular
uptake of 67Ga: one transferrinreceptor-
dependent and the other
with the independent mechanism accounting
for less than 1% of the uptake.[
14] Increasing concentrations of
transferrin are associated with a progressive
and marked increase in the
cellular uptake of 67Ga. This transferrin-
mediated uptake of 67Ga can be
blocked by a monoclonal antibody to
the transferrin receptor.
These data suggest that iron and
gallium share a common transport
mechanism-transferrin and the transferrin
receptor. Exposure of HL60
cells to transferrin-gallium complexes
results in a decreased cellular uptake
of iron and a subsequent arrest in cell
growth. The cytotoxicity of gallium
is increased by its binding to
transferrin; this cytotoxicity can be
reversed by transferrin-iron but not by
other transferrin forms. Gallium
may also impair the intracellular release
of iron from transferrin by interfering
with processes responsible for
intracellular acidification, such as
ATP-dependent endosomal acidification.[
The inhibition of cellular proliferation
by gallium is due, in part, to the
inhibition of ribonucleotide reductase,
an iron-containing enzyme responsible
for the reduction of ribonucleotides
to deoxyribonucleotides, a ratelimiting
step in DNA synthesis.[18,19]
Iron is required for the activity of
Gallium inhibits ribonucleotide reductase
by at least two mechanisms.
First, a gallium-induced decrease in
cellular iron uptake at the transferrin
receptor results in lower amounts of
intracellular iron available for the irondependent
activity of the M2 (R2) subunit
of ribonucleotide reductase.Exposure
of cells to transferrin-gallium
complexes results in a diminution of
the M2 subunit tyrosyl radical ESR
(electron spin resonance) signal on
ESR spectroscopy. The markedly
diminished ESR signal can be fully
restored if ferrous ammonium sulfate
is added to cell lysates, indicating that
gallium interferes with the incorporation
of iron into the R2 subunit.[19,23]
Furthermore, cells exposed to
transferrin-gallium complexes incorporate
significantly less 14C-adenosine
into DNA and contain significantly
smaller deoxyribonucleotide pools
than control cells. Second, gallium
appears to inhibit ribonucleotide reductase
directly via competitive inhibition
of substrate interaction with the
Following exposure to gallium, the
morphologic appearance of CCRFCEM
cells displays features characteristic
of apoptosis, including chromatin
condensation and nuclear fragmentation.[
24] Apoptotic cell death
increased directly with increasing
concentrations of gallium. In addition,
DNA cleavage into oligonucleosomal
fragments was observed after 48 hours
when cells were incubated with
gallium and analyzed for DNA fragmentation
via electrophoresis. The
gallium-induced apoptosis could be
prevented by the addition of ferrous
ammonium sulfate, showing that iron
deprivation played a role in triggering
More recent experiments indicate
that exposure of cells to gallium leads
to the release of cytochrome c from
the mitochondria and the activation of
caspase-3, leading to apoptosis.
Preliminary evidence suggests that
gallium may act on the mitochondria.
Findings from recent studies that used
an RNA differential display technique
and Northern blotting to identify
possible genetic differences between
CCRF-CEM cells sensitive or resistant
to growth inhibition by gallium nitrate
suggested that gallium-resistant cells
displayed an increase in nucleotide
sequences sharing homology with
the mitochondrial DNA control
region. Ongoing studies are
providing additional insights into the
mechanism of action of gallium
relating to the induction of apoptosis.
Targeting of Lymphoma Cells
In vitro, gallium nitrate inhibits the
growth of lymphoma cell lines in a
concentration-dependent manner. Targeting
of gallium (as transferrin-gallium)
to lymphoma cells is most likely
related to the high densities of transferrin
receptors known to exist on cells
in non-Hodgkin's lymphoma.
Transferrin receptors are present in
increased numbers on proliferating
cells.[17,28-31] Furthermore, the
density of transferrin receptors is
increased in more aggressive lymphomas.[
32-35] This process may be
related to additional growth demands
that require more iron or to transferrin
receptors conferring a type of selective
growth advantage in these cells.
Antitumor Activity in
Monotherapy at Various Dosing
In phase I studies of gallium nitrate in patients with advanced cancer, antitumor activity was noted in patients with lymphoma, soft-tissue sarcoma, or small-cell lung cancer.[36,37] Phase I studies of gallium nitrate investigated escalating doses and various dosing schedules, including single brief (15- to 30-minute) IV infusions administered every 2 to 3 weeks, daily brief infusions for 3 days administered every 2 weeks, and continuous IV infusions for 7 consecutive days administered every 3 to 5 weeks.[36- 40] Brief IV infusions and higher doses (> 700 mg/m2) were associated with adverse gastrointestinal effects, hypocalcemia, pulmonary edema, and renal insufficiency. Consequently, gallium nitrate doses recommended for phase II study were 300 mg/m2/d as a 7-day continuous IV infusion every 3 to 5 weeks or 700 mg/m2 by brief IV infusion every 2 to 3 weeks. In phase II studies, the continuous 7-day IV infusion of gallium nitrate administered via a peripheral indwelling catheter was shown to have improved tolerability, including a lower and acceptable incidence of renal toxicity.[41-43] Several phase II studies of gallium nitrate demonstrated significant activity in lymphoma and bladder cancer and minor activity in small-cell lung cancer.[37,41,44-47] The Southwest Oncology Group evaluated gallium nitrate in 38 patients with malignant lymphoma, including diffuse and nodular non-Hodgkin's lymphoma and Hodgkin's disease. Patients received gallium nitrate (700 mg/m2) by IV infusion over 30 minutes every 2 weeks. To minimize renal toxicity, patients were given 2,000 mL of fluid IV or orally within 12 hours prior to gallium nitrate infusion, with an additional 500 mL of normal saline IV within 2 hours of gallium nitrate infusion. All patients were to receive a minimum of two cycles. Of the 38 patients, 33 were fully evaluable; the remaining 5 patients died 4 to 13 days after treatment began. The median age of patients was 49 years (range: 18 to 76 years), and the median number of prior regimens was 3 (range: 1 to 7 regimens). Response was defined as at least a 50% reduction in the sum of the diameters of measured lesions, lasting for at least 1 month. Two of 10 patients with diffuse histiocytic, 2 of 6 patients with diffuse poorly differentiated, and 2 of 6 patients with diffuse mixed non-Hodgkin's lymphoma had a partial response. The duration of response lasted from 3 to 11 months. No responses were observed in patients with diffuse well-differentiated (n = 2), diffuse undifferentiated (n = 2), nodular poorly differentiated (n = 3), or nodular histiocytic non-Hodgkin's lymphoma (n = 1). One of seven patients (14%) with Hodgkin's disease had a partial response. Of the seven patients who responded, three had not responded to prior chemotherapy regimens, suggesting that gallium nitrate was not cross-resistant with other chemotherapeutic drugs. Sites of disease response included lymph nodes (n = 7), liver (n = 2), lungs (n = 1), and skin (n = 1). Toxicity was acceptable and included leukopenia (n = 4), thrombocytopenia (n = 4), gastrointestinal effects (n = 9), and renal toxicity (n = 5) in some patients; most toxicities were mild or moderate. Investigators at Memorial Sloan- Kettering Cancer Center evaluated gallium nitrate administered as a continuous IV infusion. The results of this study indicated that a 7-day infusion of gallium nitrate is active and well tolerated in patients with relapsed or refractory malignant lymphoma. This study was performed in two parts: the phase I component was a doseseeking study conducted to determine the appropriate dose, and the phase II component was conducted to evaluate the efficacy and tolerability of the chosen dose. A total of 64 patients participated in the study: 27 patients in the phase I and 37 patients in the phase II part of the study. The median age of patients was 42 years (range: 17 to 70 years), and the median Karnofsky performance status was 60 (range: 50 to 80). All patients had received extensive prior chemotherapy; the mean number of prior cytotoxic drugs used was 9 (range: 4 to 15 drugs), and the mean number of prior regimens was 3 (range: 1 to 8 regimens). The phase I study examined 4 dose levels of gallium nitrate (200, 250, 300, and 400 mg/m2/d) administered as a continuous IV infusion for 7 days. The incidence of gastrointestinal and renal toxicities increased with the higher dose. At the 400-mg/m2 dose, 3 of 10 patients developed an increase in serum creatinine levels of 1.5 mg/dL or higher; however, this increase was observed in only 1 of 7 patients receiving the 300-mg/m2 dose. Also, at the 400-mg/m2 dose, 4 of 10 patients experienced mild nausea that significantly impaired oral fluid intake. Therefore, the 300-mg/m2 dose was selected for evaluation in the phase II study. Forty-seven patients were evaluable for response to treatment in the phase II study. Overall, 34% (16/47) of patients had objective responses. Response rates in histologic subtypes of non-Hodgkin's lymphoma ranged from 40% to 50% (Table 1). Overall, treatment was well tolerated. Although renal toxicity was the most serious adverse event (Table 2), it was reversible in all instances; two patients needed short-term hemodialysis before renal function recovered. Three patients with serum creatinine concentrations 4.0 mg/dL or higher had received gentamicin during treatment with gallium nitrate. Based on this observation, the concurrent use of nephrotoxic drugs, including aminoglycosides, during gallium nitrate therapy is not advised. Hypocalcemia was observed within 3 to 4 days of treatment initiation in two-thirds of all patients and lasted several weeks. Most patients were asymptomatic; however, a few patients developed symptoms and required oral or parenteral calcium supplements. Hypomagnesemia also occurred occasionally but less frequently than hypocalcemia. Myelosuppression was somewhat difficult to evaluate because of confounding factors, such as prior treatment and varying degrees of myelophthisis or splenomegaly. However, of 39 patients with normal blood counts at baseline, only 3 developed a leukocyte count less than 2,500/μL and only 1 patient developed a platelet count less than 50,000/μL at any point during the study. Pulmonary complications (n = 9) included pleural effusions and interstitial lung infiltrates. Infectious organisms were identified in three cases, and all but one case resolved after empirical treatment. Mild, transient, asymptomatic hyperchloremic respiratory alkalosis was also observed in some patients. Combination Therapy With Hydroxyurea
In vitro, the cytotoxic effects of gallium nitrate are synergistic with those of hydroxyurea, fludarabine (Fludara), interferon-alpha, and gemcitabine (Gemzar).[18,48-50] The combination of gallium nitrate and hydroxyurea, both of which inhibit ribonucleotide reductase, is synergistic in vitro against both lymphoid and myeloid leukemic cell lines.[18,48] Thus, a clinical trial was undertaken to evaluate the efficacy and toxicity of gallium nitrate plus hydroxyurea in patients with refractory non-Hodgkin's lymphoma. Fourteen patients with advanced lowor intermediate-grade lymphoma were treated with one of the following four doses for 7 days every 3 to 4 weeks (at least three patients were treated at each level): (1) gallium nitrate (200 mg/m2/d) by continuous IV infusion plus oral hydroxyurea (500 mg/m2/d); (2) gallium nitrate (250 mg/m2/d) plus hydroxyurea (1,000 mg/d); (3) gallium nitrate (300 mg/m2/d) plus hydroxyurea (1,000 mg/d); or (4) gallium nitrate (350 mg/m2/d) plus hydroxyurea (1,000 mg/d). The median age of the patients was 64 years (range: 53 to 89 years). All patients had been heavily pretreated. The patients completed a median of 2 (range: 1 to 6) treatment cycles (one cycle = 7 days). Tumor regression was observed in 10 of 14 patients (1 complete response, 1 near-complete response, 4 partial responses, and 4 minor responses). Excluding patients with minor responses, the overall response rate was 43% (6/14 patients). The median duration of response was 7 weeks (range: 3 to 38 weeks). Responses were not confined to a particular histologic subtype; cytotoxic activity was observed in both low- and intermediate-grade lymphomas. The response to treatment can be rapid; a dramatic shrinkage in an abdominal nodal mass was observed in one patient after just one treatment cycle. Although it was hoped that 67Ga scanning would predict treatment responsiveness, no correlation was identified between tumor localization of 67Ga and tumor response to gallium nitrate. However, two patients with negative 67Ga scans did not respond to gallium nitrate. Overall, toxicities were mild, and minimal myelosuppression occurred. As expected, the most common toxicities were hypocalcemia and diarrhea. The most serious toxicities were anemia and reversible nephrotoxicity. Of four patients with nephrotoxicity, one patient had received prior treatment with cisplatin and one patient had a long history of diabetes mellitus that may have caused occult diabetic nephropathy. Another patient was unable to maintain adequate fluid intake because of anorexia. Transient, decreased visual acuity was observed in two patients. General Toxicity
In general, the toxicity of gallium nitrate does not overlap with that of other drugs commonly used for the treatment of malignant lymphoma. In particular, myelosuppression is minimal. Mild to moderate anemia has been observed; however, its direct relationship to gallium nitrate is not entirely clear because all patients treated with gallium nitrate have received myelosuppressive agents previously. No evidence of cumulative nephrotoxicity was observed in patients who received the drug for more than 14 months with adequate hydration.[ 41] Nephrotoxicity can be ameliorated or prevented with adequate hydration during treatment and by avoiding concomitant use with other nephrotoxic agents. Transient, mild to moderate hypophosphatemia may also occur and may require oral phosphorus supplements. Optic neuritis has occurred rarely in patients receiving gallium nitrate.[ 42,45,51] However, when the drug is administered at the recommended dose and frequency, its incidence is similar to that observed with other chemotherapeutic agents, such as cisplatin, carboplatin (Paraplatin), paclitaxel, and etoposide. Conclusion Gallium nitrate is a promising agent in the treatment of non-Hodgkin's lymphoma. Its mechanism of action involves drug delivery via transferrin and the transferrin receptor. Galliumtransferrin complexes target lymphoma cells because they express high numbers of transferrin receptors on their surfaces. Following cellular uptake of gallium, ribonucleotide reductase is inhibited indirectly via cellular iron depletion and also directly via competitive inhibition of substrate interaction with the enzyme. During a single-agent phase II study in patients with relapsed lymphoma, response rates of 40% to 50% in various histologic subtypes of non- Hodgkin's lymphoma were noted with continuous-infusion gallium nitrate administered over 7 days. Continuousinfusion gallium nitrate is well tolerated and is not associated with significant myelosuppression. The response rates to gallium nitrate in non-Hodgkin's lymphoma compare favorably with other single agents used in the treatment of patients with relapsed or refractory disease, including bleomycin, cyclophosphamide (Cytoxan, Neosar), doxorubicin,[ 54] and vincristine. A multicenter US phase II trial is currently under way to study further the effects of gallium nitrate in patients with refractory low- or intermediategrade non-Hodgkin's lymphoma. This study is evaluating gallium nitrate (200 to 300 mg/m2/d) for 7 days every 3 weeks by continuous IV infusion using a portable infusion pump. Future studies may include evaluating the efficacy and toxicity of gallium nitrate in combination with fludarabine, rituximab (Rituxan), and gemcitabine; gallium nitrate may serve as a replacement for platinum in some salvage regimens. Because of its apparent lack of cross-resistance with other drugs and its nonoverlapping toxicity profile, gallium nitrate is well suited for use in combination chemotherapy regimens. Ongoing investigations are studying other possible mechanisms of action of gallium nitrate, including the identification of additional molecular targets and the possibility of predicting treatment response through the use of complementary DNA microarrays. Further knowledge of the mechanisms of action of this drug may help to determine its optimal use in patients with lymphoma.
2. Green MA, Welch MJ: Gallium radiopharmaceutical chemistry. Int J Rad Appl Instrum B 16:435-448, 1989.
3. Hedley DW, Tripp EH, Slowiaczek P, et al: Effect of gallium on DNA synthesis by human T-cell lymphoblasts. Cancer Res 48:3014- 3018, 1988.
4. Foster BJ, Clagett-Carr K, Hoth D, et al: Gallium nitrate: The second metal with clinical activity. Cancer Treat Rep 70:1311-1319, 1986.
5. Rosenberg B, VanCamp L, Trosko JE, et al: Platinum compounds: A new class of potent antitumor agents. Nature 222:385-386, 1969.
6. Hart MM, Adamson RH: Antitumor activity and toxicity of salts of inorganic group IIIa metals: Aluminum, gallium, indium, and thallium. Proc Natl Acad Sci U S A 68:1623- 1626, 1971.
7. Hart MM, Smith CF, Yancey ST, et al: Toxicity and antitumor activity of gallium nitrate and periodically related metal salts. J Natl Cancer Inst 47:1121-1127, 1971.
8. Clausen J, Edeling CJ, Fogh J: 67Ga binding to human serum proteins and tumor components. Cancer Res 34:1931-1937, 1974.
9. Hara T: On the binding of gallium to transferrin. Int J Nucl Med Biol 1:152-154, 1974.
10. Sephton RG, Harris AW: Gallium-67 citrate uptake by cultured tumor cells, stimulated by serum transferrin. J Natl Cancer Inst 54:1263-1266, 1975.
11. Aulbert E, Gebhardt A, Schulz E, et al: Mechanism of 67Ga accumulation in normal rat liver lysosomes. Nuklearmedizin 15:185- 194, 1976.
12. Vallabhajosula SR, Harwig JF, Siemsen JK, et al: Radiogallium localization in tumors: Blood binding and transport and the role of transferrin. J Nucl Med 21:650-656, 1980.
13. Larson SM, Rasey JS, Allen DR, et al: Common pathway for tumor cell uptake of gallium- 67 and iron-59 via a transferrin receptor. J Natl Cancer Inst 64:41-53, 1980.
14. Chitambar CR, Zivkovic Z: Uptake of gallium-67 by human leukemic cells: Demonstration of transferrin receptor-dependent and transferrin-independent mechanisms. Cancer Res 47:3929-3934, 1987.
15. Makkonen N, Hirvonen MR, Savolainen K, et al: The effect of free gallium and gallium in liposomes on cytokine and nitric oxide secretion from macrophage-like cells in vitro. Inflamm Res 44:523-528, 1995.
16. Berggren MM, Burns LA, Abraham RT, et al: Inhibition of protein tyrosine phosphatase by the antitumor agent gallium nitrate. Cancer Res 53:1862-1866, 1993.
17. Chitambar CR, Seligman PA: Effects of different transferrin forms on transferrin receptor expression, iron uptake, and cellular proliferation of human leukemic HL60 cells: Mechanisms responsible for the specific cytotoxicity of transferrin-gallium. J Clin Invest 78:1538- 1546, 1986.
18. Chitambar CR, Matthaeus WG, Antholine WE, et al: Inhibition of leukemic HL60 cell growth by transferrin-gallium: Effects on ribonucleotide reductase and demonstration of drug synergy with hydroxyurea. Blood 72:1930-1936, 1988.
19. Chitambar CR, Narasimhan J: Targeting iron-dependent DNA synthesis with gallium and transferrin-gallium. Pathobiology 59:3-10, 1991.
20. Thelander L, Reichard P: Reduction of ribonucleotides. Annu Rev Biochem 48:133- 158, 1979.
21. Reichard P: From RNA to DNA, why so many ribonucleoside reductases? Science 260:1773-1777, 1993.
22. Chitambar CR, Narasimhan J, Guy J, et al: Inhibition of ribonucleotide reductase by gallium in murine leukemic L1210 cells. Cancer Res 51:6199-6201, 1991.
23. Narasimhan J, Antholine WE, Chitambar CR: Effect of gallium on the tyrosyl radical of the iron-dependent M2 subunit of ribonucleotide reductase. Biochem Pharmacol 44:2403- 2408, 1992.
24. Ul-Haq R, Wereley JP, Chitambar CR: Induction of apoptosis by iron deprivation in human leukemic CCRF-CEM cells. Exp Hematol 23:428-432, 1995.
25. Chitambar CR, Wereley JP, Matsuyama S: Mechanisms of antineoplastic activity of gallium nitrate in lymphoma: Protein ubiquitination and the induction of apoptosis through a Bax and mitochondrial pathway (abstract 5317). Proc Am Assoc Cancer Res 45:1226, 2004.
26. Chitambar CR, Wereley J, Tsao L, et al: Iron proteins as targets to modulate tumor cell growth: New insights into the cytotoxicity of gallium—a modulator of iron metabolism. Proceedings of the 6th Internet World Congress on Biomedical Sciences, 2000; at Castilla La Mancha University, Spain. Available from URL: http://www.uclm.es/inabis2000/symposia/ files/141/index.htm.
27. Esserman L, Takahashi S, Rojas V, et al: An epitope of the transferrin receptor is exposed on the cell surface of high-grade but not lowgrade lymphomas. Blood 74:2718-2729, 1989.
28. Hamilton TA, Wada HG, Sussman HH: Identification of transferrin receptors on the surface of human cultured cells. Proc Natl Acad Sci U S A 76:6404-6410, 1979.
29. Larrick JW, Cresswell P: Modulation of cell surface iron transferrin receptors by cellular density and state of activation. J Supramol Struct 11:579-586, 1979.
30. Frazier JL, Caskey JH, Yoffe M, et al: Studies of the transferrin receptor on both human reticulocytes and nucleated human cells in culture: Comparison of factors regulating receptor density. J Clin Invest 69:853-865, 1982.
31. Trowbridge IS, Lopez F: Monoclonal antibody to transferrin receptor blocks transferrin binding and inhibits human tumor cell growth in vitro. Proc Natl Acad Sci U S A 79:1175-1179, 1982.
32. Habeshaw JA, Lister TA, Stansfield AG, et al: Correlation of transferrin receptor expression with histological class and outcome in non-Hodgkin lymphoma. Lancet 1:498-501, 1983.
33. Pileri S, Gobbi M, Rivano MT, et al: Immunohistological study of transferrin receptor expression in non-Hodgkin's lymphoma. Br J Haematol 58:501-508, 1984.
34. Oudemans PB, Brutel de la Riviere G, Hart GA, et al: Determination of transferrin receptors on frozen sections of malignant Bcell lymphomas by immunofluorescence with a monoclonal antibody. Cancer 58:1252-1259, 1986.
35. Medeiros LJ, Picker LJ, Horning SJ, et al: Transferrin receptor expression by non- Hodgkin's lymphomas: Correlation with morphologic grade and survival. Cancer 61:1844- 1851, 1988.
36. Bedikian AY, Valdivieso M, Bodey GP, et al: Phase I clinical studies with gallium nitrate. Cancer Treat Rep 62:1449-1453, 1978.
37. Samson MK, Fraile RJ, Baker LH, et al: Phase I-II clinical trial of gallium nitrate (NSC- 15200). Cancer Clin Trials 3:131-136, 1980.
38. Hall SW, Yeung K, Benjamin RS, et al: Kinetics of gallium nitrate, a new anticancer agent. Clin Pharmacol Ther 25:82-87, 1979.
39. Krakoff IH, Newman RA, Goldberg RS: Clinical toxicologic and pharmacologic studies of gallium nitrate. Cancer 44:1722-1727, 1979.
40. Kelsen DP, Alcock N, Yeh S, et al: Pharmacokinetics of gallium nitrate in man. Cancer 46:2009-2013, 1980.
41. Warrell RP Jr, Coonley CJ, Straus DJ, et al: Treatment of patients with advanced malignant lymphoma using gallium nitrate administered as a seven-day continuous infusion. Cancer 51:1982-1987, 1983.
42. Warrell RP Jr, Danieu L, Coonley CJ, et al: Salvage chemotherapy of advanced lymphoma with investigational drugs: Mitoguazone, gallium nitrate, and etoposide. Cancer Treat Rep 71:47-51, 1987.
43. Chitambar CR, Zahir SA, Ritch PS, et al: Evaluation of continuous-infusion gallium nitrate and hydroxyurea in combination for the treatment of refractory non-Hodgkin's lymphoma. Am J Clin Oncol 20:173-178, 1997.
44. Crawford ED, Saiers JH, Baker LH, et al: Gallium nitrate in advanced bladder carcinoma: Southwest Oncology Study Group. Urology 38:355-357, 1991.
45. Seidman AD, Scher HI, Heinemann MH, et al: Continuous infusion gallium nitrate for patients with advanced refractory urothelial tract tumors. Cancer 68:2561-2565, 1991.
46. Keller J, Bartolucci A, Carpenter JT Jr, et al: Phase II evaluation of bolus gallium nitrate in lymphoproliferative disorders: A Southeastern Cancer Study Group Trial. Cancer Treat Rep 70:1221-1223, 1986.
47. Weick JK, Stephens RL, Baker LH, et al: Gallium nitrate in malignant lymphoma: A Southwest Oncology Group Study. Cancer Treat Rep 67:823-825, 1983.
48. Myette MS, Elford HL, Chitambar CR: Interaction of gallium nitrate with other inhibitors of ribonucleoside reductase: Effects on the proliferation of human leukemic cells. Cancer Lett 129:199-204, 1998.
49. Lundberg JH, Chitambar CR: Interaction of gallium nitrate with fludarabine and iron chelators: Effects on the proliferation of human leukemic HL60 cells. Cancer Res 30:6466-6470, 1990.
50. Chitambar CR, Wereley JP, Ul-Haq R: Synergistic inhibition of T-lymphoblastic leukemic CCRF-CEM cell growth by gallium and recombinant human α-interferon through action on cellular iron uptake. Cancer Res 54:3224-3228, 1994.
51. Webster LK, Olver IN, Stokes KH, et al: A pharmacokinetic and phase II study of gallium nitrate in patients with non-small cell lung cancer. Cancer Chemother Pharmacol 45:55- 58, 2000.
52. Blum RH, Carter SK, Agre K: A clinical review of bleomycin—A new antineoplastic agent. Cancer 31:903-914, 1973.
53. Stutzman L, Ezdinli EZ, Stutzman MA: Vinblastine sulfate vs cyclophosphamide in the therapy for lymphoma. JAMA 195:111- 116, 1966.
54. Cimo PL, Rudders RA, Hensleigh D: A clinical trial of Adriamycin in the malignant lymphomas. Cancer 34:1571-1575, 1974.
55. Desai DV, Ezdinli EZ, Stutzman L: Vincristine therapy of lymphomas and chronic lymphocytic leukemia. Cancer 26:352-359, 1970.