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PubMed1997

Treatment of polycythemia vera: use of 32P alone or in combination with maintenance therapy using hydroxyurea in 461 patients greater than 65 years of age. The French Polycythemia Study Group.

Despite myelosuppression, polycythemic (PV) patients greater than 65 years of age have a high risk of vascular complications, and the leukemic risk exceeds 15% after 12 years. Is the addition of low-dose maintenance treatment with hydroxyurea (HU) after radiophosphorus (32P) myelosuppression able to decrease these complications? Since the end of 1979, 461 patients were randomized to receive (or not) low-dose HU (5 to 10 mg/kg/d), after the first 32P-induced remission, and were observed until death or June 1996. Maintenance treatment very significantly prolonged the duration of 32P-induced remissions and reduced the annual mean dose received to one-third. However, despite this maintenance, 25% of the patients had an excessive platelet count and the rate of serious vascular complications was not decreased, except in the most severe cases with short-term relapse of polycythemia. Furthermore, the leukemia rate was significantly increased beyond 8 years and a significant excess of carcinomas was also observed. The continuous use of HU did not decrease the risk of progression to myelofibrosis (incidence of 20% after 15 years). Life expectancy was shorter (a median of 9.3 years v 10.9 years with 32P alone), except in the most severe cases (initial 32P-induced remission lasting <2 years) in which maintenance treatment moderately prolonged the survival by reducing the vascular risk. In most cases of PV, in which the duration of the first 32P-induced remission exceeded 2 years, the introduction of HU maintenance did not reduce the vascular risk. Although it considerably decreased the mean dose of 32P received, HU maintenance therapy significantly increased the leukemia and cancer risks and reduced the mean life expectancy by 15%. However, in cases with more rapid recurrence, the introduction of maintenance treatment reduced the vascular risks and moderately prolonged survival. The use of HU as a maintenance therapy is therefore only justified in this situation.

Actuarial Analysis↗

PubMed1997

Decrease of very late activation antigen-4 and CD36 on reticulocytes in sickle cell patients treated with hydroxyurea.

Sickle cell disease (SCD) is characterized by repeated vaso-occlusive events, which result in substantial morbidity. Abnormal adhesion of sickle red blood cells (RBC) to the vascular endothelium is postulated to play a role in the pathogenesis of vaso-occlusion. Two adhesion receptors, very late activation antigen-4 (VLA-4) and CD36, are found in unusually high numbers on sickle cell reticulocytes and do mediate adhesion of sickle RBC to endothelium. Hydroxyurea (HU) therapy results in fewer vaso-occlusive episodes, and we postulated that HU-related modulation of VLA-4 and CD36 receptors may contribute to its clinical benefit. Using flow cytometry, eight patients were followed from the onset of HU treatment through a mean treatment length of 200 +/- 49 days. Mean corpuscular volume and percent fetal hemoglobin (Hb F) increased from 87% +/- 6% to 98% +/- 9% and 6.6% +/- 3.9% to 12.7% +/- 5.6%, respectively. The percentage of reticulocytes expressing VLA-4 decreased from 29.0% +/- 5.9% to 14.9% +/- 2.3% (P = .0003). Two thirds of the total decrease in VLA-4 expression occurred after 10 weeks of HU and plateaued by 20 weeks. Changes in VLA-4 expression occurred before substantial increases in Hb F. The percentage of reticulocytes expressing CD36 decreased from 55.3% +/- 6.4% to 42.6% (P = .0046). Changes in adhesion receptor expression were not caused by a decrease in reticulocytosis with HU therapy. This report is the first to associate a decrease in adhesion receptor expression with a therapy known to reduce the clinical severity of SCD.

Adolescent↗

PubMedDate not supplied

The interaction of hydroxyurea and ionizing radiation in human cervical carcinoma cells.

PURPOSE: The results from prior in vitro and in vivo studies and recent phase 3 clinical trials suggest a significant potential role for hydroxyurea (HU) as a clinical radiosensitizer for cervix cancer. However, a detailed study of possible cellular mechanisms of radiosensitization in human cervix cancer cells as a consequence of dose and timing of HU and ionizing radiation (IR) has not been performed. This in vitro study analyses the interactions of HU and IR in a human cervical carcinoma cell line, Caski. MATERIALS AND METHODS: Exponentially growing Caski cells were continuously exposed to clinically achievable but minimally cytotoxic concentrations of HU (0.3-3.0 mM) for various time intervals (6, 12, 18, 24, and 30 hours) up to one population doubling time either prior to or immediately following IR (2-8 Gy). The radiation survival data were analyzed using our modification of the linear-quadratic model to test for an interaction (greater than additive). The effects of HU alone, IR alone, and the combination on cell cycle progression and on apoptotic cell death in exponentially growing Caski cells were measured. RESULTS: We report a significant HU-IR interaction (radiosensitization) based on the sequence of HU exposure (post- > pre-IR) and with increasing concentrations of HU (0.3-3.0 mM), but no effect on radiosensitization with the duration of exposure to HU for up to one cell population doubling (6-30 hours). HU concentration has a significant effect on both alpha and beta linear-quadratic values in the post-IR sequences. Exposures of exponentially growing Caski cells to 1 mM and 3 mM HU alone result in a complete block in early S phase throughout the 30-hour exposure, while 0.3 mM HU causes a transient early S-phase block over the initial 12 to 18 hours of exposure. HU alone has no effect on cell cycle progression in G1 or G2/M populations but results in a large apoptotic population (31% following 1 mM HU x 30 hours), which appears to be the principal mechanism of drug cytotoxicity in these cells. IR alone (4 or 6 Gy) results in a significant G2 delay for 6 to 18 hours following IR but no G1 delay and a small apoptotic population at 30 hours post-IR (5.4% vs 2.1% in non-IR controls). The use of HU (0.3 or 1.0 mM) following IR (4 or 6 Gy) results in a significantly larger G2 delay compared with IR alone, but with only an additive effect on the apoptotic population. CONCLUSIONS: These in vitro data demonstrate that radiosensitization of Caski cells is more significant with post-IR exposures to clinically achievable concentrations of HU. This HU-IR interaction is associated with an increased G2 delay, suggesting a reduction in IR damage repair. However, this interaction appears to be independent of the cytotoxicity (principally by apoptosis) from HU alone.

Apoptosis↗

PubMed1997

Determinants of fetal hemoglobin response to hydroxyurea.

Fetal hemoglobin (HbF) modulates the phenotypic diversity of sickle cell anemia (HbSS), and the prevalence of many disease complications is related to the level of HbF. Hydroxyurea (HU) increases HbF levels in many patients. Adults with HbSS have HbF levels that may differ by two orders of magnitude, suggesting the possibility of genetic modulation of gamma-globin gene expression. In HbSS, the beta-globin gene haplotype is associated with HbF. Polymorphisms present in cis-acting elements are usually linked to the haplotype, suggesting that within a haplotype, mutations in these areas are uncommon mechanisms of HbF modulation in patients with untreated HbSS. In a multicenter trial of HU in HbSS, we examined genetic elements, patient characteristics, and follow-up features to determine their association with changes in HbF. Following treatment, F cells increased in HU-treated patients compared with controls. The increases in the HbF level at 2 years were greatest in patients who had the highest baseline counts of reticulocytes and neutrophils, two or more episodes of study-defined myelotoxicity, and absence of a Bantu haplotype. However, after 2 years, half of the patients had no or only trivial increments in HbF. The ability to respond to HU may depend on bone marrow reserve, or the capacity of the marrow to withstand moderate doses of HU with acceptable myelotoxicity. Baseline reticulocyte and neutrophil counts may be a measure of this marrow reserve. Sustained HbF increases during HU treatment can occur in individuals with bone marrow reserve sufficient to respond to the myelotoxicity of this agent with the evolution of a population of high HbF-producing erythroblasts.

Adult↗

PubMed1997

Mechanism of action of hydroxyurea in the management of sickle cell anemia in adults.

In a randomized, placebo-controlled clinical trial, treatment with hydroxyurea (HU) reduced crisis rates in adult patients with severe sickle cell anemia. No serious acute toxicity was seen, but the safety of long-term therapy could not be evaluated. The rationale for the use of HU was based on its ability to increase fetal hemoglobin (HbF) synthesis and the inhibitory effect of HbF on polymerization of sickle cell hemoglobin. Surprisingly, final HbF levels in patients assigned to HU did not differ markedly from their pretreatment levels (5% v 9%). As Steinberg et al showed, when HU patients were divided into quartiles based on final HbF levels, those in the highest quartile had an 18% mean HbF, while those in the lowest quartile had a mean of only 4%. Higher HbF levels were associated with lower crisis rates, but the association was not statistically significant. Further analyses suggested noncompliance of patients in the lower HbF quartiles in the later months of the study as a significant factor responsible for the difference in HbF levels. When HU patients were divided into quartiles based on their 2-year crisis rates, those with the fewest crises had lower neutrophil counts and higher mean corpuscular volumes (MCVs) and F-cell counts; similar but less marked changes were seen in patients assigned to placebo. Multivariable analyses showed a significant relationship between crisis rate and, in the early months of the study, F-cell count and, in later months, MCV. Lower neutrophil counts were associated with lower crisis rates in all months of the study. The HbF in F cells inhibits their sickling and decreases the likelihood of vaso-occlusion and infarction. If infarction does occur, lower neutrophil counts may limit the extent of tissue destruction and the severity of pain. Further study is needed to clarify the interplay of these two factors as mediators of the effect of HU in lowering crisis rates in sickle cell anemia.

Adult↗

PubMed1997

Hydroxyurea in children: present and future.

Children with sickle cell anemia provide the best opportunity to assess the efficacy of hydroxyurea (HU) in preventing complications and progressive organ damage. The possibility of treating infants with sickle cell disease (SCD) to inhibit the development of organ dysfunction may be the most important future use of HU. The possibility even exists that instituting HU in the neonate may stop the fetal-to-adult globin chain switch and thus markedly change the clinical phenotype of SCD. Recent data suggest HU may also be especially beneficial in children not only by increasing hemoglobin F (HbF), but also by altering the adhesive receptors expressed on red blood cells and vascular endothelium, further increasing the possibility that vasculopathy can be prevented. Six pediatric trials that included small numbers of severely ill patients have been reported recently. All patients received relatively standard HU doses. All studies reported a significant improvement in HbF and mean corpuscular volume and a mild to marked increase in hemoglobin. The clinical response to HU in children with SCD seems to be consistent. The National Institutes of Health pediatric multicenter trial should help answer the question of short-term HU toxicity; however, questions remain concerning long-term risks, such as carcinogenesis, gametogenesis, marrow toxicity, growth retardation, and chromosomal damage. Long-term studies are needed to answer these questions. The future treatment of most children with SCD with HU alone or in combination with other agents looks promising, and long-term trials are warranted.

Anemia, Sickle Cell↗

PubMed1997

Hydroxyurea therapy for diverse pediatric populations with sickle cell disease.

Hydroxyurea (HU) is the first widely used treatment to have an impact on the severity of disease in adult patients with sickle cell anemia, but limited data are available for younger patients or those with variant genotypes. We reviewed 324 months of experience with HU in 16 patients from 5.3 to 18.4 years of age treated for 6 to 50 months. The major toxicity was reversible neutropenia. Linear growth continued unchanged, and all patients gained weight. Hematologic results were similar to those reported in adults with increases in mean corpuscular volume (MCV) and total and fetal hemoglobin (HbF). We noted that the maximal hematologic effects occurred at less than the maximum dose. Clinically, patients experienced an 80% reduction in episodes of acute chest syndrome and a reduced need for blood transfusion, as well as a 30% decrease in the number of hospitalizations for painful events during HU therapy compared with an equivalent number of months before HU. These highly statistically significant results confirmed the value of HU in ameliorating the severe clinical course of pediatric patients. Similar effects were observed in three patients with sickle beta degrees-thalassemia, sickle beta+-thalassemia, and S-O Arab. Recurrent acute splenic sequestration and progressive symptomatic osteonecrosis were observed during HU. Thus, HU may not prevent the development of complications once organ damage is present. The challenge remains to determine when and to which pediatric patients with sickle cell disease HU should be offered.

Adolescent↗

PubMed1997

Treatment of polycythemia vera: the use of hydroxyurea and pipobroman in 292 patients under the age of 65 years.

Nonradiomimetic drugs, hydroxyurea (HU) and pipobroman (Pi), were administred to relatively young subjects with polycythemia vera (PV) in an attempt to decrease the leukemogenic risk observed in patients treated with 32P. Clinical safety, hematological efficacy, risk of carcinoma or leukemia, and frequency of progression to myelofibrosis have not yet been defined in long-term studies, and no comparative studies of HU and Pi have been conducted. Since 1980, 292 patients with PV diagnosed before the age of 65 years were randomized to receive treatment with HU (25 mg/kg/d, followed by low-dose maintenance) or Pi (1.2 mg/kg/d, followed by low-dose maintenance). Patients were followed until death or until May 1997. Drug tolerance was often poor; leg ulcers and buccal aphthous ulcers (with HU) and gastric pain and diarrhea (with Pi) sometimes required treatment change, mainly in the HU arm. Hematological stability, especially in terms of platelet count, was very often insufficient with HU (45% of cases), but the risk of thrombo-embolic event was similar in both arms. Actuarial survival was similar in the two arms and shorter than that of the reference population. The risk of leukemia was approximately 10% at the 13th year, with no significant difference between the two arms. The risk of carcinoma (when excluding the skin cancers) was similar in both groups. There was a high risk of progression to myelofibrosis in the patients treated by HU, which was significantly higher than with Pi.

Antineoplastic Agents↗

PubMed1997

Hydroxyurea can be used to increase mouse c-kit+Thy-1. 1(lo)Lin-/loSca-1(+) hematopoietic cell number and frequency in cell cycle in vivo.

The DNA synthesis inhibitor hydroxyurea (HU) was administered to determine whether it induces changes in the cell-cycle status of primitive hematopoietic stem cells (HSCs)/progenitors. Administration of HU to mice leads to bone marrow accumulation of c-kit+Thy-1.1(lo)Lin-/loSca-1(+) (KTLS) cells in S/G2/M phases of the cell cycle. HU is a relatively nontoxic, reversible cell-cycle agent that can lead to approximately a threefold expansion of KTLS cells in vivo and approximately an eightfold increase in the number of KTLS cells in S/G2/M. HSCs in HU-treated mice have undiminished multilineage long-term and short-term clonal reconstitution activity.

Animals↗

PubMed1976

[Hydroxyurea synchronization of cellular proliferation in the esophageal epithelium of mice with tumors].

The synchronizing effect of hydroxyurea on the passage of the esophagus epithelia cells through the stage of the DNA synthesis and mitosis was investigated in albino mice bearing sarcoma. Dinrnal variations in the number of epithelial cells at these stages of the mitotic cycle were taken into consideration. Two mutually complementary indices for the measurement of the shifts in the cell population and the rate of the synchronization are used. Two cell groups which passed the S-phase and mitosis synchronously were found in artificial synchronization in the esophageal epithelium. The synchronization indices characterizing the first group were lower than control. In the second group the cell count during the DNA synthesis was double as compared with the number of cells synthesizing DNA in natural synchronization; however, the rate of the changes in the synchronism was the same in the experimental and control groups.

Animals↗

PubMed1998

Treatment of myeloproliferative disorders with hydroxyurea: effects on red blood cell geometry and deformability.

Hydroxyurea (HU) is used in suppressing the bone marrow and producing fetal-like red blood cells (RBCs). These RBCs are large in size and may theoretically disturb the microcirculation. In five patients with myeloproliferative disorders (MPD), the RBC geometry and deformability were analyzed before and after 6 to 8 months of HU treatment. In untreated MPD, the RBC geometry and filterability was normal. After HU, the RBC membrane area increased 24% and the cell volume increased 39% (P <.005). This change resulted in a 12% increase in the minimum cylindrical diameter (MCD). From a static bending model of initial deformation, the RBC diametrical cross-section had a significantly increased section modulus. However, this increase in profile stiffness was compensated for by its larger projected cell area and, thus, pressure load on the RBC corpuscle. The resulting resistance to initial deformation therefore remained unchanged after HU. These findings were tested experimentally; with 3-microm filter membranes, HU treatment caused a significant increase in flow resistance (P <.02), in accordance with MCD. However, with 5-microm pores, no difference was seen, again in consonance with the theoretical findings of initial deformation. Because most capillaries are larger than 3 microm, we suggest that HU is acceptable from a perspective of cellular microrheology.

Aged↗

PubMed1998

[Chronic myelogenous leukemia with long-term hypoplasia induced by alpha-interferon and hydroxyurea].

A 48-year-old woman was admitted with chronic myelogenous leukemia in November, 1996 and was treated with hydroxyurea (HU), because of marked leukocytosis; WBC 404,000/microliter. On January 29, 1997, administration of HU was stopped, and treatment of alpha-interferon (IFN alpha) was started with 6x 10(6)U, every day. However, the WBC count rose from 19,600/microliter to 56,800/microliter, and the combination of IFN and 2,000 mg of HU was started on February 4. The dose of HU was reduced to 500 mg on February 27, and the IFN administration was reduced to 3 times a week from April 4, because the WBC count was less than 10,000/microliter. Pancytopenia was revealed in May. The bone marrow biopsy specimen demonstrated marked hypoplastic changes, and chromosome analysis of bone marrow cells showed Philadelphia chromosome in all 20 metaphases. Treatment was interrupted for 7 months, but hematologic parameters did not recover. There were 9 cases reported in detail with bone marrow hypoplasia induced by IFN. One patient received IFN alone and 8 patients received anti-cancer drugs before treatment of IFN. We concluded that great care must be taken for IFN treatment of CML.

Antineoplastic Agents↗

PubMed1998

Fetal hemoglobin and F-cell responses to long-term hydroxyurea treatment in young sickle cell patients. The French Study Group on Sickle Cell Disease.

We have studied the cellular and molecular responses to long-term hydroxyurea (HU) treatment in 29 severely affected young patients with sickle cell disease (mean age, 10.9 +/- 4.1 years). Patients received HU at 20 mg/kg/d on 4 consecutive days per week initially, with a monthly escalated dose avoiding marrow-toxicity (mean steady-state dose, 34.2 +/- 4.6 mg/kg/d) for 12 to 36 months (mean duration, 22 months). The studied parameters were hemoglobin F (HbF), F reticulocytes (F retics), F cells, the amount of HbF per F cell (F/F cell), polymer tendency at 40% and 70% oxygen saturation, and hemolysis. Initial HbF (Fi) was dispersed (from 0.85% to 13.9%). HbF increased in all patients but 1. HbF at maximal response (Fmax) reached a sustained level varying from a 1.5-fold to a 16-fold Fi after a variable delay (6 to 24 months). Fmax was not related to HU dosage, but triangle upF (Fmax - Fi) was strongly correlated to triangle upMCV (MCVmax - MCVi). HbF increase resulted from the increase of both F cells and F/F cell. In this rather short series, Fi and Fmax were not significantly associated with age, gender, or beta-globin haplotype. Neither Fmax nor triangle upF was related to bone marrow reserve, as measured by baseline reticulocyte or neutrophil counts. However, Fmax was highly dependent on Fi. When patients are individualized into three groups according to Fmax (group 1, Fmax >20% [12 patients]; group 2, 10% < Fmax < 20% [11 patients]; group 3, Fmax <10% [5 patients]), Fi is significantly different between groups, being the highest in group 1. In addition, the best responders (group 1) were significantly different from patients in the two other groups with higher levels of total hemoglobin, decreased bilirubin, and decreased polymer tendency.

Adolescent↗

PubMedDate not supplied

In vitro toxicity of A 3'-azido-3'-deoxythymidine and hydroxyurea combination on normal myeloid progenitors.

Hydroxyurea (HU) appears to increase 3'-azido-3'-deoxythymidine (AZT) antiretroviral activity and cytotoxicity by inhibiting thymidilate synthesis. The combination of AZT and HU may therefore be of clinical usefulness. We evaluated the in vitro hemotoxicities of different combinations of AZT and HU in comparison with the hemotoxicities exerted by either of the two drugs alone. Peripheral blood granulocyte macrophage committed progenitors (CFU-GM) of healthy donors were selected as targets of hemotoxicity. Both AZT and HU separately had a dose-dependent inhibitory effect on the in vitro growth of normal circulating CFU-GM. The combination of the two drugs induced a statistically significant synergistic cytotoxicity. In fact, addition of HU induced a remarkable reduction of AZT ID50. Thus, future clinical application of AZT, HU combination should take into account the greater hemosuppressive action of the combination in respect to that observed following administration of either drug alone.

Cell Survival↗

PubMed1998

[Myositis caused by hydroxyurea in a patient with chronic myelogenous leukemia].

A 59-year-old man with chronic myelogenous leukemia (CML) had a white-blood-cell (WBC) count of 55,400/microliter when admitted in July 1997, and was placed on oral hydroxyurea (HU) of 1,500 mg/day. Treatment with 600 MU/day of interferon alpha (IFN alpha) was started on August 5. HU was discontinued when the patient's WBC count dropped to 8,100/microliter on August 18. However, HU was resumed about a month later, after his WBC count increased to 10,100/microliter, but discontinued when the patient started to complain of chills, high fever, and bilateral femoral pain. HU treatment was initiated again one week later, after the patient's WBC count had begun rising but ceased again after he experienced chills, high fever, and bilateral femoral pain. The patient's myogenetic enzymes were found to be increasing the following day, and a lymphocyte stimulation test (LST) with HU showed a high stimulation index of 41.7%. The elevation of myogenetic enzymes and the results of the LST suggested that myositis due to HU was the cause of the patient's clinical manifestations. His myositis spontaneously disappeared after HU was discontinued. Although the patient is no longer receiving HU, IFN alpha has brought his CML under control. To our knowledge, this is the first reported case of myositis caused by HU.

Antineoplastic Agents↗

PubMed2002

Optimisation of 5-fluorouracil (5-FU)/cisplatin combination chemotherapy with a new schedule of hydroxyurea, leucovorin, 5-FU and cisplatin (HLFP regimen) for metastatic oesophageal cancer.

To improve the efficacy and tolerance of the 5-fluorouracil (5-FU)/cisplatin combination in metastatic esophageal cancer, we designed a new therapeutic schedule, the HLFP regimen. 42 patients with metastatic oesophageal adenocarcinoma (n=10) or squamous cell carcinoma (n=32) were prospectively enrolled in the study. All had bidimensionally measurable disease. The HLFP regimen consisted of twice-monthly oral administration of hydroxyurea 1 g/m(2) on days 0, 1 and 2; a 2-h infusion of leucovorin 200 mg/m(2) and a bolus of 5-FU 400 mg/m(2) followed by a 22-h infusion of 5-FU 600 mg/m(2) on days 1 and 2; and, every two cycles, 80 mg/m(2) cisplatin on day 3. Relief of dysphagia and other symptoms were monitored, together with body weight changes. Major objective responses were observed in 24 patients (57%, 95% Confidence Interval (CI): 42-72%), including four complete responses (10%). The median progression-free survival and overall survival times were 8 and 12.7 months, respectively. Weight gain was observed in 48% of patients, and dysphagia improved in 76%. Grade 3-4 toxicity occurred in 40% of patients, with grade 4 neutropenia in 12% and grade 3 thrombocytopenia, vomiting and diarrhoea in 7-9% of patients. There were no treatment-related deaths. These results suggest that the HLFP regimen is an active and well-tolerated chemotherapy for metastatic oesophageal carcinoma.

Adenocarcinoma↗

PubMed1996

Bicyclic N-hydroxyurea inhibitors of 5-lipoxygenase: pharmacodynamic, pharmacokinetic, and in vitro metabolic studies characterizing N-hydroxy-N-(2,3-dihydro-6-(phenylmethoxy)-3-benzofuranyl)urea.

A series of N-hydroxyurea derivatives have been prepared and examined as inhibitors of 5-lipoxygenase. Oral activity was established by examining the inhibition of LTB4 biosynthesis in an ex vivo assay in the mouse. The pharmacodynamic performance in the mouse of selected compounds was assessed using an ex vivo LTB4 assay and an adoptive peritoneal anaphylaxis assay at extended pretreat times. Compounds with an extended duration of action were re-examined as the individual enantiomers in the ex vivo assay, and the (S) enantiomer of N-hydroxy-N-[2,3-dihydro-6-(phenylmethoxy)-3-benzofuranyl]urea, (+)-1a (SB 202235), was selected as the compound with the best overall profile. Higher plasma concentrations and longer plasma half-lives were found for (+)-1a relative to its enantiomer in the mouse, monkey, and dog. In vitro metabolic studies in mouse liver microsomes established enantiospecific glucuronidation as a likely mechanism for the observed differences between the enantiomers of 1a. Enantioselective glucuronidation favoring (-)-1a was also found in human liver microsomes.

Animals↗

PubMed1999

Elimination of extrachromosomal c-myc genes by hydroxyurea induces apoptosis.

Hydroxyurea (HU) increases extrachromosomal DNA elimination in tumor cell lines. The c-myc oncogene is one of the many relevant amplified genes contained within the extrachromosomal DNA compartment. Spontaneous loss of amplified copies of c-myc induces terminal differentiation and apoptosis in the human HL-60 leukemia cell lines. In the present study, we evaluate HU's ability to induce apoptosis by eliminating extrachromosomally located c-myc oncogene in human tumor cell lines. The consequences of eliminating extrachromosomal DNA by HU were explored in two different cell lines using the TdT assay and acridine orange/ethidium bromide labeling. COLO 320 clone 3 and COLO 320 clone 21 cell lines contain the same number of amplified copies of c-myc oncogene, but located respectively on extrachromosomal DNA, and intrachromosomally in homogeneously staining regions. HU induced apoptosis in the COLO 320 clone 3 cell line by a time and concentration dependent mechanism but could not induce apoptosis in the COLO 320 clone 21 cell line. These results suggested that HU-induced apoptosis in COLO 320 cell lines depends on elimination of extrachromosomal amplified copies of the c-myc oncogene. The ability of HU to eliminate extrachromosomally amplified copies of the c-myc oncogene and to induce apoptosis should be considered when targeting malignancies with amplification of the c-myc oncogene in an extrachromosomal site.

Journal Article↗