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PubMed1992

An overview of the clinical experience with hydroxyurea.

In the more than 30 years since hydroxyurea was first evaluated clinically, a number of diverse and unique applications have been identified for its use. Some of these applications were apparent to investigators almost from the beginning, while others are still evolving 3 decades later as a result of ongoing research. An overview of clinical experience with hydroxyurea provides an historical perspective on a period encompassing virtually the entire era in which anticancer chemotherapy has been a recognized discipline. The critical role of the ribonucleotide reductase reaction in the regulation of DNA synthesis makes this enzyme a particularly important target site for antineoplastic therapy. The sustained interest in hydroxyurea, however, has been the result of careful clinical observations as well as basic laboratory studies, which support current attempts to identify additional uses for the drug. This overview describes the clinical development of hydroxyurea, discusses current indications, and briefly describes areas of ongoing research that may expand the clinical indications for hydroxyurea.

Humans↗

PubMed1992

High-dose hydroxyurea in autologous bone marrow transplantation: a promising "new" agent.

Hydroxyurea is an antineoplastic drug with a broad spectrum of clinical activity and minimal nonhematopoietic toxicity. It potentiates the cytotoxicity of alkylating agents and topoisomerase II active drugs in vitro and in vivo. It is not susceptible to alkylating agent-specific or multidrug-type resistance. We have therefore added high-dose oral hydroxyurea to widely used autologous bone marrow transplantation combination chemotherapy regimens for large cell lymphoma and metastatic breast cancer. Seventeen patients with primary-refractory or refractory-relapse large cell lymphoma received oral hydroxyurea (1.5 g/m2 every 6 hours for 12 doses) added to carmustine/cyclophosphamide/etoposide (BCV). Twelve patients with metastatic breast cancer received the same dose oral hydroxyurea added to cyclophosphamide and thiotepa. Mucositis severe enough to require parenteral narcotics was seen in over half of the patients, but none required intubation for airway maintenance. A thrombotic thrombocytopenic purpura-like hemorrhagic syndrome occurred in six patients and was fatal for three. With the BCV/hydroxyurea regimen, this syndrome was seen with the same frequency as with BCV alone. Death from rapidly progressive disease or toxicity occurred in seven of 29 patients (24%). For patients with 6 months' minimum follow-up, four of 12 (33%) of the metastatic breast cancer patients remain in complete response (median follow-up, 15 months), and four of 17 (24%) refractory large cell lymphoma patients remain in complete response (median follow-up, 10 months). High-dose hydroxyurea may increase the effectiveness of standard autologous bone marrow transplantation regimens without substantially increasing toxicity.

Administration, Oral↗

PubMed1992

The evolution of hydroxyurea therapy in chronic myelogenous leukemia.

The evolution of hydroxyurea as a chemotherapeutic agent has been unique. Hydroxyurea inhibits synthesis of DNA, has antitumor activity, and is myelosuppressive. It has attained a significant role in the management of chronic myelogenous leukemia. A nonrandomized comparison of busulfan and hydroxyurea concluded that hydroxyurea was the preferable agent in the treatment of chronic myelogenous leukemia and was associated with less life-threatening toxicity. Because of its systemic effects, hydroxyurea is also used in the treatment of polycythemia and psoriasis.

Humans↗

PubMed1988

Hyperthermia blocks reversibility of hydroxyurea and bipyridine induced synergistic inhibition of DNA biosynthesis in P388 murine leukemia cells.

The influence of hyperthermia (42 degrees C) on the reversibility of hydroxyurea- and the iron-chelator 2,2'-bipyridine-induced synergistic inhibition of DNA biosynthesis was studied in intact P388 murine lymphocytic leukemia cells in vitro. The cytotoxicity caused by hydroxyurea alone and in combination with bipyridine for 3 h at 37 degrees C and 42 degrees C was found to be completely reversible. However, the inhibition of DNA biosynthesis was irreversible when hydroxyurea- and iron-chelate-treated and washed cells at 37 degrees C were subjected to hyperthermia at 42 degrees C. A potentiation in DNA biosynthesis was also observed when the P388 cells were subjected to hyperthermia along with the combination of hydroxyurea and 2,2'-bipyridine. These effects are probably due to the heat-sensitive nature of the ribonucleotide reductase enzyme, the target site of the effect of hydroxyurea and 2,2'-bipyridine.

2,2'-Dipyridyl↗

PubMed1978

Differential effect of hydroxyurea on a ribonucleotide reductase system.

Infection of Escherichia coli with phage T4 induces a large increase in ribonucleotide reductase activity. We show that hydroxyurea inhibits T4-induced CDP, ADP, UDP, and GDP reductase activities in vitro. Moreover, there are significant differences in the degree of inhibition of each ribonucleotide reductase activity. The reductase activities for CDP and ADP are more sensitive to hydroxyurea than those for UDP and GDP, particularly at high hydroxyurea molarities. As little as 5 x 10(-4)M hydroxyurea lowers CDP and ADP reductase activities to 25 to 30% whereas as much as 0.5 M hydroxyurea is needed to lower UDP and GDP reductase activities to 50%.

Coliphages↗

PubMed1987

Hydroxyurea-induced cell death as related to cell cycle in mouse and human T-lymphoma cells.

The association between DNA precursor synthesis, cell cycle perturbations, and cell death caused by the anticancer drug hydroxyurea was investigated in mouse and human T-lymphoma cells. Hydroxyurea inhibits the enzyme ribonucleotide reductase, leading to decreased deoxyribo nucleoside triphosphate pools and an accumulation of cells in early S-phase of the cell cycle. We wished to clarify the mechanism of cell death caused by hydroxyurea in concentrations that can be obtained therapeutically. At a 60-microM concentration of the drug, giving 25% growth inhibition during 24 h, no increase in the number of dead cells was observed as determined by cell flow calculations and density gradient centrifugation. However, the removal of hydroxyurea led to 10-30% cell loss during the following 12-h period. In parallel, there was an increase in DNA precursor levels and a rapid progression of cells through S- and G2 phases of the cell cycle. The isolated dead cells showed no overrepresentation of any cell cycle phase. The results demonstrate that, although the toxic effects of low concentrations of hydroxyurea are minimal, the drug-induced unbalanced growth state can cause substantial cell death during a posttreatment period.

Animals↗

PubMed1995

Modulation of 5-FU/alpha-interferon with high-dose continuous infusion hydroxyurea.

Biochemically modulated 5-fluorouracil (5-FU) regimens are active against several gastrointestinal malignancies. Hydroxyurea is an inhibitor of the enzyme ribonucleotide reductase. Despite successful in vitro studies, studies combining oral hydroxyurea with 5-FU based regimens have failed to demonstrate clinical synergy. Based on the pharmacokinetic properties of hydroxyurea, continuous exposure to the drug may be required to reproduce the synergy observed in vitro. We will review the pharmacology of hydroxyurea and the rationale for the modulation of 5-FU/alpha-interferon (IFN) with high-dose continuous infusion hydroxyurea.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1977

Comparison of hydroxyurea and excess thymidine as synchronizing agents in cultures of L5178Y mouse lymphoma cells.

Comparison of double hydroxyurea and hydroxyurea-excess thymidine blockades as synchronizing procedures in cultured L5178Y cells revealed that hydroxyurea mimics the effect of thymidine as regards the degree of the resulting synchrony evaluated by the mitotic index and 3H-thymidine incorporating activity. However, the peaks of the mitotic and 3H-incorporating activity appear later after thymidine than after hydroxyurea blockade and the initial maximum incorporation of 3H-deoxycytidine into DNA was about twice higher in thymidine- than in hydroxyurea-treated cells. On the other hand, the timing of 14C-formate incorporation into purine DNA bases was closely similar in both cell populations.

Animals↗

PubMed1997

Painful oral ulcers with hydroxyurea therapy.

Five patients treated with hydroxyurea for various haematological malignancies developed multiple painful oral ulcers. Their neutrophil counts were either normal or elevated. The ulcers disappeared with cessation of hydroxyurea. Oral ulcers recurred when hydroxyurea was resumed in one of the patients. As the patients were unable to tolerate this painful side effect, hydroxyurea had to be discontinued. Appearance of painful oral ulceration seems to be independent of dosing rate or total cumulative dose of hydroxyurea.

Adolescent↗

PubMed1998

Multiple squamous cell carcinomas of the skin during long-term treatment with hydroxyurea.

Hydroxyurea is a chemotherapeutic agent used extensively for myeloproliferative disorders. Cutaneous side effects have been described during long-term hydroxyurea treatment. We described the occurrence of multiple squamous cell skin carcinomas in a patient treated with hydroxyurea for chronic myelogenous leukemia. The lesions were removed and the hematological therapy switched to busulfan. In a previously reported case, the development of cutaneous epithelial cancers required the discontinuation of hydroxyurea, in addition to the surgical excision of the neoplastic lesions. Since squamous cell carcinoma is a malignant cutaneous neoplasm that can metastatize, the surveillance of skin changes is advisable during hydroxyurea treatment.

Aged↗

PubMed1996

Methyl DNA adducts, DNA repair, and hypoxanthine-guanine phosphoribosyl transferase mutations in peripheral white blood cells from patients with malignant melanoma treated with dacarbazine and hydroxyurea.

Dacarbazine (DTIC) is a DNA-methylating drug used in the treatment of malignant melanoma. Among the DNA dducts induced by DTIC are N7-methylguanine (N7-meG) and O6-methylguanine (O6-meG). The latter adduct, in particular, may be important in the mutagenic as well as the cytotoxic activity of DTIC. Repair of O6-meG is carried out by the enzyme O6-alkylguanine-DNA-alkyltransferase (AGT) by a process which results in its autoinactivation. N7-meG is lost from DNA partly spontaneously and partly by enzymatic depurination followed by excision repair of the resulting apurinic site. The purpose of this study was to determine the in vivo kinetics of formation and repair of O6-meG and N7-meG and the changes in AGT in peripheral WBCs with repeated doses of DTIC, and to determine the effects on these processes of concomitant administration of hydroxyurea. In addition, we examined the induction of mutations at the HPRT gene locus. Thirty-four patients with malignant melanoma received 1.0 g/m2 DTIC i.v. every 3 weeks. Hydroxyurea was added to the second and subsequent doses of DTIC in 19 patients. The concentrations of O6-meG, N7-meG, and AGT in peripheral blood lymphocytes were determined up to 24 h after each of the first two doses of DTIC. Mutations at the HPRT gene locus were determined using the T-cell clonal assay. Peak O6-meG levels were detected 1 and 4 h after the first and second dose of DTIC, respectively. AGT concentrations declined to 56.7% (range, 40.3-76.9%) and 55.0% (range, 45.4-58.9%) of pretreatment levels 24 h after the first and second doses of DTIC, respectively, and were still approximately 25%below their initial levels just prior to administration of the second dose of DTIC. An increase in formation of O6-meG was observed at all time points after the second dose of DTIC (P = 0.0001), which was not affected by cotreatment with hydroxyurea (P > 0.5). There was a negative correlation between pretreatment AGT levels and the O6-meG concentration at 24 h after therapy (r = -0.554, P = 0.014). N7-meG levels peaked at 6 h after DTIC therapy and were not significantly influenced by the cycle number. Cotreatment with hydroxyurea tended to be associated with lower levels of N7-meG (P = 0.08). There was no correlation between either O6-meG or N7-meG levels and the grade of neutropenia. On the basis of a limited series of blood samples analyzed, there was no firm evidence that chemotherapy with DTIC resulted in induction of HPRT mutations in lymphocytes. In conclusion, repeated administrations of DTIC resulted in higher concentrations of O6-meG, probably due to reduction in cellular AGT. Hydroxyurea did not significantly influence the kinetics of O6-meG, and N7-meG adduct formation. There was no significant induction of HPRT gene mutations with DTIC. This study suggests that sequencing of DTIC doses should be evaluated using the time course of cellular AGT depletion and DNA adduct formation to achieve higher cytotoxic efficiency.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1996

Treatment of advanced adenocarcinomas of the exocrine pancreas and the gallbladder with 5-fluorouracil, high dose levofolinic acid and oral hydroxyurea on a weekly schedule. Results of a multicenter study of the Southern Italy Oncology Group (G.O.I.M.).

BACKGROUND: To date there is no established chemotherapeutic treatment for patients with unresectable locally advanced and/or metastatic carcinomas of the exocrine pancreas or the gallbladder. A multicenter Phase II trial has been performed by the Southern Italy Oncology Group with the aim of evaluating the clinical effectiveness and tolerability of weekly 5-fluorouracil (5-FU) in modulation with intravenous (i.v.) high dose levofolinic acid and oral hydroxyurea. METHODS: A total of 70 patients fulfilling the standard eligibility for a Phase II study were enrolled in the trial. Forty patients had advanced pancreatic adenocarcinoma and 30 had advanced gallbladder carcinoma. The treatment schedule was: levofolinic acid, 100 mg/m2, in 500 mL of normal saline over 2-hour infusion followed by 5-FU, 600 mg/m2 i.v. bolus, and oral hydroxyurea, 1000 mg/m2, for 1 day every week for 6 consecutive weeks followed by 15 days of rest. RESULTS: Among the 40 patients with pancreatic adenocarcinoma, 5 (12.5%; 95% confidence level [CL], 8.5-16.5%) showed a partial response with a median duration of 5.6+ months, and 13 had stable disease. Twenty-two patients progressed. Median survival was 5.8 months. Among patients with advanced gallbladder carcinoma, 9 of 30 had a partial response (30%; 95% CL, 26-34%) with a median duration of 6.5 months, and 8 (27%) had stabilization of disease. Thirteen patients showed progressive disease. Median overall survival was 8 months. Toxicity was mild, with Grade 1 to 2 leukopenia and gastrointestinal toxicity the most frequent side effects. No chemotherapy-related deaths were observed. CONCLUSIONS: 5-FU in modulation with i.v. levofolinic acid and oral hydroxyurea on a weekly schedule is well tolerated by the vast majority of patients with locally advanced and/or metastatic carcinoma of the pancreas or the gallbladder. Although response rate and overall survival for patients with pancreatic adenocarcinoma are far from acceptable, the 30% overall response rate achieved in patients with advanced gallbladder carcinoma suggests that 5-FU in modulation with levofolinic acid and hydroxyurea is active in this neoplasm. The combination of modulated 5-FU with other antineoplastic drugs seems worthy of clinical testing in further controlled trials.

Adenocarcinoma↗

PubMed1980

Use of hydroxyurea in the measurement of DNA repair by the BND cellulose method.

Hydroxyurea inhibition is a convenient method of suppressing replicative DNA synthesis for DNA excision-repair measurement by the BND cellulose technique. Nonetheless, hydroxyurea can introduce artefacts by direct reaction with repair-inducing compounds and by long-term inhibition of the overall repair process. A simple technique of overcoming these problems is described. Cells are reacted with repair-inducing compounds in the absence of hydroxyurea, the cells are washed free of inducer, hydroxyurea is added to 2 mM, and after a short period to establish replication inhibition, 3H dThd is added and repair measured over a one-hour incubation period.

Acetoxyacetylaminofluorene↗

PubMed1979

Cell cycle analysis of sodium butyrate and hydroxyurea, inducers of ectopic hormone production in HeLa cells.

Sodium butyrate and hydroxyurea, effective inhibitors of DNA synthesis in HeLa cells, cause these cells to produce increased levels of the ectopic glycopeptide hormones human chorionic gonadotropin (hCG), follicle stimulating hormone (FSH), and free alpha chains for these hormones. The objective of this study was an assessment of the role of modulation of cell cycle events in the action of these two chemical agents. A variety of experimental approaches was employed to obtain a clear view of the drugs' effects on cells located initially in all phases of the cell cycle. Cells in early G1, G2, or M phase at time of addition of either inhibitor were not arrested at early time points, but by 48 hours became collected at a location characteristic for each drug, near the G1-S phase boundary. Flow microfluorometry (FMF) and thymidine labeling index revealed that butyrate-treated cells arrested late in G1 phase very close to S phase, while hydroxyurea-blocked cells continued to early S phase. Both inhibitors prevented cells originally in S phase from reaching mitosis. S cells exposed to hydroxyurea were killed by 48 hours, but those growing in 5 mM butyrate progressed to the end of S or G2 phase where they became irreversibly arrested although not removed from the monolayer. Analysis of the cell cycle location and viability of each subpopulation resulting from 48 hour exposure to butyrate or hydroxyurea is important for the study of the function of each cellular subset. Treatment of HeLa cells with lower concentrations of butyrate (1 mM) resulted in slowed yet exponential growth. Fraction labeled mitosis (FLM) analysis shows that this is a result of prolongation of the G1 phase.

Butyrates↗

PubMed1978

Correlation of log P with molecular connectivity in hydroxyureas: influence of conformational system on log P.

The correlation of log P (in octanol--water) with the nonempirical, topologically dependent, calculated molecular connectivity index (1chiv) delineates substituted hydroxyureas into two families of linearly related groups of compounds. The first group, composed of the 3-substituted ethyl, n-propyl, and n-butyl analogs, is more hydrophilic than the 1-substituted methyl and ethyl and the 3-substituted isopropyl and tert-butyl analogs. The unsubstituted model compound hydroxyurea appears between the two groups in equal volumes of octanol. In octanol--water ratios of 5:1, log P approaches the range of the more hydrophilic group in high concentrations and becomes more lipophilic (similar to the other group) in lower concentrations. The differences in the relative hydrophilicities--lipophilicities of the two groups are rationalized in terms of the equilibri of internally hydrogen-bonded, conformers to those that allow optimal interactions with solvent, water, or other hydroxyurea molecules. The concentration dependency observed with hydroxyurea appears to be due to the ease of interconversion of intermolecularly bonded conformers to those interacting with water, whereas the involvement of internally bonded conformers, which are apparently present to a greater degree in lower concentrations, increases the relative lipophilicity.

Hydroxyurea↗

PubMed1987

Hydroxyurea plus pelvic radiation versus placebo plus pelvic radiation in surgically staged stage IIIB cervical cancer.

Forty-five evaluable patients with stage IIIB carcinoma of the uterine cervix were entered into a prospective, double-blind, randomized study to evaluate the possible radiation-potentiating properties of hydroxyurea. All patients were documented to be without para-aortic lymph node metastasis by pretherapy staging para-aortic lymphadenectomy. The original plan of therapy was for continuous therapy (200 rads/day) of 6,000 rads of pelvic radiation for 6 weeks plus intrauterine radium. However, 16 patients received 6,000 rads in 8 weeks by split-course therapy (2-week rest after 3,000 rads) plus radium. Twenty-nine patients received the planned continuous therapy. The median dose of pelvic radiation for patients who received continuous therapy or split-course radiation was 6,000 rads. Leukopenia (WBC less than 2,500/mm3) was significantly increased in the patients given hydroxyurea as compared to those given placebo (P less than .001). There was no statistically significant difference relative to anemia, thrombocytopenia, radiation skin reaction, diarrhea, or radiation-induced complications requiring surgical correction. The estimated 5-year progression-free survival rate for the combined, continuous, and split-course radiation therapy hydroxyurea patients was 60%, and its was 52% for the corresponding placebo patients (P = .49). However, the estimated 5-year progression free survival rate for the correctly treated patients (continuous therapy) was 91% for the hydroxyurea group and 60% for the placebo group (P less than .06).

Adult↗

PubMed2005

Enalapril and hydroxyurea therapy for children with sickle nephropathy.

Proteinuria in children with sickle cell anemia (SCA) is an early sign of sickle nephropathy, and portends the development of nephrotic syndrome and chronic renal failure. Enalapril has been shown to reduce proteinuria in adult patients with SCA, but the potential benefits of hydroxyurea in this clinical setting have not been reported. A single institution retrospective analysis was performed. Children with sickle nephropathy were identified, and the laboratory effects of enalapril and hydroxyurea therapy were evaluated in children with substantial proteinuria. Three children developed proteinuria at 8 +/- 1 years of age. Pre-treatment laboratory studies included a low serum albumin (2.8 +/- 0.8 g/dl) and a highly elevated urine protein/creatinine ratio (6.9 +/- 3.7, normal <0.2). Enalapril treatment for 3.0 +/- 1.3 years normalized serum albumin (3.9 +/- 0.3 g/dl) without significant changes in serum potassium, serum creatinine, or systolic blood pressure. However, urine protein/creatinine remained elevated in the nephrotic range (1.6 +/- 0.7). The addition of hydroxyurea therapy for 3.5 +/- 1.2 years increased fetal hemoglobin levels (7.0 +/- 3.6% to 21.0 +/- 3.2%) and was associated with a near-normal urine protein/creatinine ratio (0.5 +/- 0.1). Enalapril therapy for children with sickle nephropathy reduces urinary protein excretion and normalizes serum albumin. Hydroxyurea therapy may further normalize the urine protein/creatinine ratio. Combination therapy should be tested prospectively in children with sickle nephropathy.

Adolescent↗

PubMed1995

Measurement of DNA integrity and structure in Xenopus embryos in the presence of hydroxyurea, actinomycin-D, and triethylenemelamine using the fluorescent probe Hoechst 33258.

Cell health assay of water quality (CHAWQ) is an assay using intracellular biomarkers measured by optical techniques. CHAWQ uses embryos of the South African clawed frog, Xenopus laevis, and optical transducers of intracellular biomarkers to obtain rapid assessment of toxicity to frog embryos. Since the biomarkers are common to all cells, CHAWQ can indicate toxicity of different classes of chemicals. Among the biomarkers used are 1) the change in synthesis rate, 2) the structure, or 3) the environment of DNA. Measurement of DNA to detect genotoxicants has previously used extracted DNA or flow cytometry to detect alterations in DNA content or configuration. We report the use of viable frog embryos and the fluorescent probe Hoechst 33258 to detect the effect of three DNA-active chemicals--actinomycin-D, hydroxyurea, and triethylenemelamine (TEM)--on DNA in intact embryos. We found that we can detect changes in the DNA in the presence of toxicants at concentrations comparable to longer-term assays but following a much shorter time of drug exposure. Actinomycin-D caused a fluorescence decrease, TEM caused a fluorescence increase, whereas hydroxyurea gave a biphasic response. Hydroxyurea caused a decrease at low concentrations and an increase at higher concentrations. Concentration-response data for TEM, hydroxyurea, and actinomycin-D generated EC50 values of 0.1 mg/ml, 1.4 mg/ml, and 6.34 micrograms/ml, respectively.

Animals↗