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PubMed1984

Adriamycin and cyclophosphamide versus hydroxyurea in advanced prostatic cancer. A randomized Southwest Oncology Group study.

Over a 24-month period, the Southwest Oncology Group (SWOG) conducted a randomized prospective chemotherapeutic trial in 158 patients with advanced prostatic cancer. Patients were initially randomized to receive either a combination of Adriamycin and cyclophosphamide (AC) or a single agent, hydroxyurea (H), and then crossed over to the other treatment on failure. Of the 137 evaluable patients, 43 (31%) had classically measurable metastatic disease in the lymph nodes, skin, chest, or liver. Focusing their efforts on this subset of patients with measurable disease, the authors of this report found the combination AC to have a superior response rate to the single agent, hydroxyurea. Objective response to AC was seen in 6 of 19 (32%) and in only one of 24 (4%) patients randomized to hydroxyurea (P = 0.06, Fisher's exact test). However, in the larger group of 137 evaluable patients, a survival advantage was not seen for those individuals treated with AC. Failure to demonstrate a survival advantage for an objectively superior drug combination would suggest the need for more active phase II agents in this disease.

Aged↗

PubMed1994

Relationship of burst-forming-unit-erythroid progenitors and their DNA-synthesis stage to fetal hemoglobin levels in hydroxyurea-treated patients with sickle cell anemia.

DNA-synthesis stage and total number of circulating burst-forming-units-erythroid (BFU-E) have been inversely correlated with hemoglobin F levels in the peripheral blood, as well as in the cells from the BFU-E-derived colonies obtained from homozygous sickle cell anemia (SS) patients during steady state. Similar studies in SS patients treated with cytotoxic agents have not been reported. However, regeneration of the erythroid marrow that follows the cytoreduction phase of chemotherapy has been suggested as one of the mechanisms of stimulation of fetal hemoglobin synthesis. Therefore, a longitudinal study of hemopoiesis in hydroxyurea-treated SS patients was conducted. Thirty-two sets of hemopoietic studies, including total circulating BFU-E and S-phase BFU-E, were obtained from three patients treated with hydroxyurea. A dose-dependent decrease in total BFU-E colonies occurred in peripheral blood of all three patients (r = -0.58, -0.85, and -0.97, respectively, with each P < 0.05). There was a strong positive correlation between hydroxyurea dose and fetal hemoglobin levels in two of the three patients who responded clinically (r = 0.89618 and 0.88632, respectively, with each P < 0.01). When data from all patients were combined (n = 32), there was a strong, inverse, linear relationship between total number of BFU-E and percentage S-phase BFU-E with fetal hemoglobin levels (r = -0.6649 and -0.7404, respectively, with each P < 0.0001). A stronger, curvilinear, multiple relationship was detected between total BFU-E and percentage S-phase BFU-E with fetal hemoglobin levels (R = 0.8351 and 0.8602 with each P < 0.0001).

Adolescent↗

PubMed1987

Comparison of synchronized Chinese hamster ovary cells obtained by mitotic shake-off, hydroxyurea, aphidicolin, or methotrexate.

Synchronized cell populations are necessary to study many aspects of cell biology. We have developed a method to obtain highly synchronized Chinese hamster ovary cell populations in S phase or G2 phase by utilizing mitotic selection followed by incubation with either hydroxyurea, aphidicolin, or methotrexate for 12 h. Flow cytometry analysis shows that the coefficient of variation in the spread of the cell population in S phase is as low as 6%. Drug toxicity studies compare the effects of the various drugs on G1 and S phase cells. The use of aphidicolin or hydroxyurea results in the most highly synchronized cell populations, but methotrexate yields inadequate synchronization. These results demonstrate that both aphidicolin and hydroxyurea are useful drugs for obtaining highly synchronized cell populations after an initial synchrony in mitosis. Aphidicolin is perhaps the best choice because of less toxicity to S phase cells when used in low concentrations.

Animals↗

PubMed2003

cDNA microarray gene expression profiling of hydroxyurea, paclitaxel, and p-anisidine, genotoxic compounds with differing tumorigenicity results.

The potential application of toxicogenomics to predictive toxicology has been discussed widely, but the utility of the approach remains largely unproven. Using cDNA microarrays, we compared the gene expression profiles produced in mouse lymphoma cells by three genotoxic compounds, hydroxyurea (a carcinogen), p-anisidine (a noncarcinogen), and paclitaxel (carcinogenicity unknown). To minimize the effect of biological variability and technological limitations, quadruplicate observations were made for each compound and a subset of genes yielding reproducible induction/repression was selected for comparison. A method was applied to attach normalized expression data to genes with a low false-discovery rate (<0.1) to yield more confidence regarding differential expression. This analysis identified genotoxicity-specific gene expression. Seven genes were consistently upregulated and 12 downregulated more than 2-fold by the three genotoxic compounds. Using additional genes, the expression pattern induced by the genotoxic noncarcinogen, p-anisidine, was readily distinguished from that associated with the genotoxic carcinogen, hydroxyurea. Comparison of paclitaxel-induced expression data to data for p-anisidine and hydroxyurea suggested that paclitaxel's profile is more similar to the genotoxic noncarcinogen. With further supporting evidence it may be possible to perform large-scale monitoring of gene expression during drug and chemical development that can provide an early warning of potential toxicological responses.

Aniline Compounds↗

PubMedDate not supplied

Treatment of terminal-phase chronic myelogenous leukemia with intermediate-dose cytarabine and hydroxyurea.

We used intermediate doses of Ara-C (IDAra-C) in the treatment of 15 patients with chronic myelogenous leukemia (CML) in blast crisis and, combined with hydroxyurea, in 20 CML patients in accelerated phase. Patients with blastic CML received intensive 5-day courses of IDAra-C 600 mg/m2 every 12 h as a 2-h infusion. Of 15 patients, three achieved complete response (CR) and three partial response (PR), for an overall response rate of 40 per cent. All patients developed severe leukopenia and thrombocytopenia, and two died in hypoplasia. Except nausea and vomiting requiring medication, other nonhematologic toxicities were uncommon. Median response duration was 4 months (range 1 to 7 months). Survival was 5 months for responders and 1.5 months for nonresponders. Patients with CML in accelerated phase were treated with two-day courses of IDAra-C 600 mg/m2 every 12 h by 2-h infusion, every two-three weeks. Daily hydroxyurea 1-1.5 g/day was administered between courses. Of 20 patients, 15 (75 per cent) achieved a good PR with rapid improvement of the symptoms of disease acceleration. The median duration of response was 11 months (range 3 to 38 months); duration was over 24 months in five patients. The median survival from the start of IDAra-C was 13 months for responders and 3.5 months for nonresponders. We conclude that IDAra-C is an effective approach for CML in terminal phase. Its use in 5-day induction courses for blast crisis CML has a response rate comparable to that achieved with high-dose Ara-C. In patients in accelerated phase, the combination of short courses of IDAra-C with hydroxyurea is a well-tolerated treatment able to improve substantially the clinical and hematologic symptoms of disease progression.

Adult↗

PubMed1977

Solvent-dependent conformational system of hydroxyureas in octanol-water and in inhibition of ribonucleotide reductase.

The carbonyl nitrogen IR absorption region of selected hydroxyureas was examined in octanol. The spectra indicated appreciably different absorptions prior to and after equilibration with water. Stability studies on the hydroxyureas indicated that the absorption differences were not due to chemical decomposition in the equilibration process but were due to solvent conformation and/or tautomeric dependency of the system. Preliminary in vitro inhibition of the enzyme ribonucleoside diphosphate reductase by selected hydroxyureas also indicated an apparent solvent dependency, which may involve the conformational and/or tautomeric properties of these agents. The implications of the solvent-dependent conformation-tautomeric system observed are discussed in relation to this property in the biological action of these agents.

Chemical Phenomena↗

PubMed1977

Synthesis and anticancer activity of novel cyclic N-hydroxyureas.

To overcome the disadvantages of hydroxyurea in anticancer therapy such as fast biotransformation and low potency, five cyclic N-hydroxyureas were synthesized. A new reaction was developed to prepare the desired products from the appropriate alkyl omega-haloalkylcarbamates with hydroxylamine. This reaction probably involves a two-step mechanism: nucleophilic substitution and intramolecular cyclization. The anticancer screening tests of these compounds were done both in vitro using tissue culture and in vivo. One compound, 1-hydroxy-1,3-diazacylohexan-2-one, had anticancer activity comparable to hydroxyurea both in vivo and in vitro.

Animals↗

PubMed1989

Hydroxyurea plus pelvic irradiation versus placebo plus pelvic irradiation in nonsurgically staged stage IIIB cervical cancer.

Twenty-five patients with FIGO stage IIIB carcinoma of the cervix were entered into a prospective, double-blinded randomized study to evaluate the possible radiation potentiating properties (i.e., improved survival) of the S phase cell cycle specific inhibitor of DNA synthesis hydroxyurea (H). In contrast to our previous randomized trial of patients with FIGO stage IIIB carcinoma of the uterine cervix who were documented to be without paraaortic lymph node metastasis by pretherapy staging paraaortic lymphadenectomy [Piver et al.: J Surg Oncol 35: 129-134, 1987], these patients either refused surgical staging or, because of medical conditions, could not undergo pretherapy paraaortic lymphadenectomy. Patients were to receive 6,000 cGy/6 weeks to the pelvis by megavoltage radiation therapy followed by 2,500 cGy to point A by intracavitary and vaginal radium/cesium. The median pelvic cGy for the Hu patients was 5,967 cGy and for the placebo patients 6,013 cGy. Leukopenia (WBC less than 2,500/mm3) significantly increased in patients given hydroxyurea as compared with those given placebo (P less than 0.0001). There was no statistically significant difference relative to anemia, thrombocytopenia, radiation skin reactions, diarrhea, or radiation induced complications requiring surgical correction. The estimated 5 year disease-free interval was 54% for the hydroxyurea patients (median not reached) and 18% for the placebo patients with a median of 11 months. Because of these results, those of our previous reports, and those of the Gynecologic Oncology Group, we believe that hydroxyruea plus pelvic radiation should be the standard against which new potential radiation sensitizers are tested.

Adult↗

PubMed1979

A teratogenicity study on hydroxyurea and diphenylhydantoin in cats.

Hydroxyurea, an antitumor drug and known teratogen in rat, miniature swine and dog, and diphenylhydantoin, a teratogen in mouse and rat, were assessed for teratogenic effects in cat. Pregnancies were induced, by synchronizing gonadotropin-stimulated estrus and ovulation with natural copulations. Hydroxyurea at 50 or 100 mg/kg, and sodium diphenylhydantoin at 1 or 2 mg/kg dosages, were administered orally in single daily doses from gestation days 10-22. Appropriate controls given empty capsules, were included for each drug. Cats were necropsied on gestation day 43. Fetuses were examined for external, visceral and skeletal malformations. Hydroxyurea at 50 mg/kg dose produced a low teratogenic activity and at 100 mg/kg a high incidence of non-pregnancy and resorptions with, consequently, fewer live fetuses. Diphenylhydantoin gave no clear evidence of teratogenicity at any test dose but was embryolethal at the maternally toxic dose of 2 mg/kg. So far, studies conducted suggest that the cat is a useful species for screening drugs and chemicals for their teratogenic potential.

Abnormalities, Drug-Induced↗

PubMed1996

Combination chemotherapy with hydroxyurea, dacarbazine (DTIC), and etoposide in the treatment of uterine leiomyosarcoma: a Gynecologic Oncology Group study.

Advanced or recurrent uterine leiomyosarcomas have traditionally been resistant to most chemotherapeutic regimens. Preliminary reports suggested the combination of hydroxyurea, dacarbazine (DTIC), and etoposide (VP-16) was sufficiently effective to warrant larger trials. In a Phase II trial undertaken by the Gynecologic Oncology Group, 39 patients with advanced or recurrent leiomyosarcoma were treated with 2 g of hydroxyurea, 700 mg/m2 of DTIC, and 300 mg/m2 of VP-16 in divided doses every 4 weeks. Thirty-eight patients were evaluable for response. Two patients experienced complete responses and five had partial responses for a total objective response rate of 18.4% (95% confidence interval: 7.7-34.3%). In general, therapy was well tolerated with moderate toxicity. Six of the seven responders had disease outside the pelvis. The combination of hydroxyurea, DTIC, and VP-16 exhibits moderate activity against uterine leiomyosarcoma.

Adult↗

PubMed1977

[Partial synchronization of tumor cells in vivo with hydroxyurea (author's transl)].

For the partial synchronization of tumor cells, Yoshida ascitic sarcoma bearing rats were treated with Hydroxyurea using two methods, one in the form of a single intraperitoneal injection (0.5 mg/g body weight) and the other by continuous intraascitic infusion over a period of 12h (1.428 mg/g body weight total dose). The synchronization obtained by continuous infusion of Hydroxyurea is superior to that by a one time injection with respect to cell accumulation in one phase of the cell cycle and in the duration of synchronous proliferation. The degree of cell loss caused by infusion depends on the concentration of Hydroxyurea. Concentrations of slightly more than the minimal inhibitory concentration of DNA synthesis cause the least damage to the tumor cells.

Animals↗

PubMed1975

Inhibition of RNA synthesis, a possible mode of the embryotoxic action of hydroxyurea.

14C-u-glucose and 32P-phosphate were given intravenously to pregnant rats, treated and untreated with hydroxyurea (HU). The incorporation of radioactivity into a variety of cell components of the embryo was measured. With this double-labelling technique it is possible to survey the effects of embryotoxic drugs on various pathways in mammalian embryos in vivo. Onset, extent and duration of the metabolic changes were measured after application of "non-teratogenic" and teratogenic doses of hydroxyurea (HU). 3 hrs after application of hydroxyurea only DNA synthesis is affected, whereas after 5 hrs RNA synthesis is also inhibited.

Abnormalities, Drug-Induced↗

PubMed1993

A phase I trial of high-dose continuous-infusion hydroxyurea.

Hydroxyurea inhibits ribonucleotide reductase, resulting in depletion of intracellular deoxynucleotide pools and inhibition of DNA repair. It has been used in a variety of malignancies and is usually given orally. Deoxynucleotide depletion is directly related to the concentration of and duration of exposure to hydroxyurea; thus, prolonged continuous infusion may result in increased therapeutic efficacy. A total of 30 patients were treated on this trial, designed to determine the maximum tolerated doses (MTD) of intravenous hydroxyurea given as a 24- or 48-h continuous infusion. The MTD for the 24-h infusion was 13,520 mg/m2 following a bolus of 1,690 mg/m2, and the mean (+/- SD) plasma steady-state concentration was 1.93 +/- 0.52 mM. For the 48-h infusion, the MTD was 17,576 mg/m2 following a bolus of 2,197 mg/m2 and the mean steady-state level was 1.43 +/- 0.31 mM. The dose-limiting toxicity on both schedules was marrow suppression manifesting as neutropenia and thrombocytopenia. Pharmacokinetic analysis revealed decreasing clearance with increasing dose, implying that drug elimination is saturable. Pharmacodynamic analysis showed a slight correlation between steady-state plasma levels and the degree of marrow suppression.

Adult↗

PubMed1990

Hydroxyurea-induced acute alveolitis in a patient with chronic myeloid leukaemia.

A number of cytotoxic agents have been implicated in the production of widespread pulmonary alveolar damage. We present a case of life-threatening alveolitis in a patient on hydroxyurea for chronic myeloid leukaemia. The clinical course suggests that the alveolitis was induced by the hydroxyurea. This is the first reported case of hydroxyurea-induced pulmonary alveolitis.

Aged↗

PubMed1996

Phase I trial of high-dose infusional hydroxyurea, high-dose infusional 5-fluorouracil and recombinant interferon-alpha-2a in patients with advanced malignancies.

The ribonucleotide reductase inhibitor, hydroxyurea (HU), augments the cytotoxic effects of 5-fluorouracil (5FU) in vitro; both drugs are synergistic with interferon-alpha (IFN) in vitro. The aim of this phase I study was to determine the maximal duration of HU, 4.3 g/m2, administered as a parenteral infusion in combination with 5FU, 2.6 g/m2 administered over 24 hrs each week, + IFN, 9 MU, subcutaneously three times per week. There were 26 patients enrolled and evaluable. This included 14 patients with colorectal cancer of whom 13 had been previously treated, and 12 patients with other refractory malignancies (pancreas, cholangiocarcinoma, hepatocellular carcinoma, renal cell carcinoma, and others), of whom 10 were previously untreated. The dose-limiting toxicity of this regimen was myelosuppression. This prohibited dose escalation of HU above the starting dose (24 hrs) on a 6-weeks-on, 2-weeks-off therapy schedule. When filgrastim, 480 microg, was administered subcutaneously on days 3-6, the duration of HU could be extended to 48 hrs on a 2-weeks-on, 1-week-off therapy schedule. There were two instances of fatal infection, one in a patient with a rectovaginal fistula with neutropenic sepsis and the second in a patient with non-neutropenic Clostridium septicum sepsis. All therapy was administered in the ambulatory setting. There were three responders, all among previously untreated patients. High-dose parenteral hydroxyurea, 4.3 g/m2 administered over 24 hrs, can be safely combined with high-dose weekly 5FU, 2.6 g/m2 over 24 hrs + IFN, 9 MU subcutaneously three times per week, without filgrastim in the ambulatory setting. Parenteral hydroxyurea, 4.3 g/m2 over 24 hrs daily x 2 can also be combined with high-dose 5FU + IFN, but requires the addition of filgrastim to avoid severe myelosuppression.

Adult↗

PubMed1983

Alterations in the components of ribonucleotide reductase in hydroxyurea-resistant hamster cells.

Two components of mammalian ribonucleotide reductase have been separated by blue dextran-Sepharose chromatography from a hydroxyurea-resistant cell line, NCR-30A2, and its parental wild type. Analysis of reductase activity in these cells and the enzyme components reveals that there are three alterations involving ribonucleotide reductase activity in NCR-30A2 cells. There is an elevation in the effector-binding (EB) component, an elevation in the non-heme-iron-containing (NHI) component, and an alteration in the NHI component that renders the enzyme less sensitive to inhibition by hydroxyurea. These findings easily account for the resistance of NCR-30A2 cells to the antitumor agent hydroxyurea, and to other drugs with a similar mode of action.

Animals↗

PubMed1987

Altered expression of ribonucleotide reductase and role of M2 gene amplification in hydroxyurea-resistant hamster, mouse, rat, and human cell lines.

Five hamster, mouse, and rat cell lines resistant to the cytotoxic effects of hydroxyurea have been characterized. All cell lines contained increased ribonucleotide reductase activity, elevated levels of the M2 component of ribonucleotide reductase as judged by electron paramagnetic resonance spectroscopy, and increased copies of M2 mRNA as determined by Northern blot analysis. Two species of M2 mRNA were detected in rodent cell lines, a high-molecular-weight species of approximately 3.4 kb in hamster and rat cells and about 2.1 kb in mouse cells. The low molecular-weight M2 mRNA was about 1.6 kb in all rodent lines. Northern blot analysis showed that the mRNA for the other component of ribonucleotide reductase, M1, was not markedly elevated in the drug-resistant cells and existed as a single 3.1-kb species. Four of the five resistant lines contained an M2 gene amplification as determined by Southern blot analysis, providing direct evidence to support earlier suggestions that hydroxyurea resistance is often accompanied by amplification of a ribonucleotide reductase gene. An increase in gene dosage was detected even in cells exhibiting only modest drug-resistance properties. No evidence for amplification of the M1 gene of ribonucleotide reductase was found. In keeping with these observations with drug-resistant rodent lines, a human (HeLa) cell line resistant to hydroxyurea was also found to contain increased levels of two M2 mRNA species (about 3.4 and 1.6 kb) and exhibited M2 gene amplification. One hamster cell line resembled the other resistant rodent lines in cellular characteristics but did not show amplification of either the M1 or M2 gene, providing an example of a drug-resistant mechanism in which an elevation of M2 mRNA has occurred without a concomitant increase in M2 gene copy number.

Animals↗

PubMed1993

Acute alveolitis induced by hydroxyurea in a patient with myeloproliferative syndrome.

Hydroxyurea is increasingly being used to control myeloproliferative disorders, in part because of its relative lack of side effects. We present a case of life-threatening alveolitis in a patient treated with hydroxyurea for myeloproliferative syndrome. Absence of exposure to other drugs and the clinical course suggest that the alveolitis was induced by hydroxyurea.

Acute Disease↗