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PubMed1981

Combined chemotherapy of head and neck squamous cell carcinomas with methotrexate, bleomycin, and hydroxyurea.

Thirty-two patients with squamous cell carcinoma of head and neck not amenable to surgery or radiotherapy were treated with a combination of methotrexate 0.6 mg/kg IV weekly, bleomycin 15 mg IV weekly, and hydroxyurea 1,000 mg/m2 three oral doses weekly. Eleven complete responses and ten partial responses of more than 50% were observed. The mean duration was 43 weeks for complete responses and 35 weeks for partial responses. Toxicity consisted in leukopenia, thrombocytopenia, nausea, vomiting, stomatitis, and cutaneous alterations. Only one patient suffered reversible lung toxicity. These results suggest that a combination of three drugs in squamous cell head and neck cancer may be more effective than a combination of bleomycin and methotrexate only.

Antineoplastic Agents↗

PubMed1975

Accumulation of replicating bacterial plasmid DNA during thymine limitation or hydroxyurea treatment.

The rate of DNA chain elongation of a thymine auxotroph of Proteus mirabilis harboring an R factor was reduced by either thymine limitation or treatment with hydroxyurea. Using CsCl density gradient centrifugation, sedimentation in sucrose gradients, and electron microscopy, it has been shown that the fraction of total R factor DNA which is in the process of replication is greatly increased when the rate of DNA chain elongation is reduced while the initiation of plasmid replication continues at the normal rate. This makes possible the isolation and characterization of replicating plasmid DNA. Electron microscopy revealed that replicating R factor DNA consists of double-branched (theta type) circular molecules.

Centrifugation, Density Gradient↗

PubMed1988

Synergistic effect of hydroxyurea and excessive thymidine on the expression of the common fragile sites at 3p14 and 16q23.

There is a synergistic effect between hydroxyurea (HU) and high concentrations of thymidine (TdR) on the induction of the common fragile sites at 3p14 and 16q23. The frequencies of expression of these fragile sites were significantly higher than in the controls when excessive TdR (0.5 mM) and HU (4 mM) were added into lymphocyte cultures in MEM medium 24 h and 2 h before harvest. Two conditions for the maximum expression of common fragile sites, such as fra(3)(p14), fra(16)(q23) are discussed. The TdR-HU fra(3)(p14)-inducing system might be modified effectively and consistently to improve the prenatal diagnosis of the fragile X syndrome.

Chromosome Fragile Sites↗

PubMed1976

Recombination and hydroxyurea inhibition of DNA synthesis in yeast meiosis.

Hydroxyurea (HU) inhibits the premeiotic DNA replication and the meiotic events that followed, namely readiness, recombination commitment, haploidisation, sporulation commitment and ascus formation. Short incubations with HU (2-4 hrs) during the premeiotic replication (i.e. starting between 3 and 6.5 hrs in sporulation medium) allow the resumption of the replication at a normal rate following the removal of the drug. The other meiotic events are similarly delayed by the approximate length of the treatment. In these experiments, intragenic recombination in ade2 reached a higher level than in the controls (x 1.3-2.0 in one pair of heteroalleles and x 3.0-4.0 in another pair). The recombination response to short HU treatments was not observed for a pair of heteroalleles in ade2 that normally shows a high level of meiotic recombination (750 per 10(6) cells), nor was the response observed in a pair of heteroalleles in lys2. HU treatments have almost no effect on sporulating cells from 8 hrs onwards. At 7-7.5 hrs the meiotic cells are very sensitive to the drug and even short treatments cause cell death and massive DNA degradation.

DNA Replication↗

PubMed1978

Comparison of thymidine, fluorodeoxyuridine, hydroxyurea, and methotrexate blocking at the G1/S phase transition of the cell cycle, studied by replication patterns.

Cultures of human amniotic fluid cells and fibroblasts were temporarily blocked by the replication inhibitors thymidine (dT) surplus, fluorodeoxyuridine (FdU), hydroxyurea (HU), or methotrexate uridine (MU). The respective arresting point at G1-S transition and the homogeneity of the blocked cell population were determined by means of BrdU replication patterns. Most variation of patterns were found after HU. After MU, cells were arrested before the onset of replication, while with dT surplus of FdU an arresting point in early S seemed more likely.

Amniotic Fluid↗

PubMed1986

A cytogenetic investigation of DNA rereplication after hydroxyurea treatment: implications for gene amplification.

Although the mechanisms leading to gene amplification are poorly understood, it has recently been proposed that the initial event of amplification is the rereplication of a variable, but relatively large, amount of the genome within a single cell cycle. We sought evidence for rereplication of DNA as a basis for gene amplification through two cytogenetic techniques: differential staining for sister-chromatid exchange analysis and premature chromosome condensation. Synchronized Chinese hamster ovary cells were incubated continuously with bromodeoxyuridine and treated with hydroxyurea (HU) when cells were approximately 2 h into the S phase. After 6 h exposure to HU, the drug was removed and at 3 h intervals thereafter metaphase cells were collected and the chromosomes were stained by the fluorescence-plus-Giemsa procedure. No staining patterns consistent with rereplication of DNA were observed. Since HU causes cytogenetic damage, the premature chromosome condensation technique was used to determine the kinetics of chromosome damage after removal of HU. Extensive G2 chromosome damage within 1 h after removal of HU from the medium was found, although cesium chloride gradient analysis showed that there was no rereplication of DNA during this time. Contrary to a previous report, these results provide no evidence that incubation of cells with HU during S phase induces rereplication of DNA within a single cell cycle. The results observed are consistent with the hypothesis that drug-induced aberrations and the subsequent abnormal segregation of chromosomal fragments are the first steps in the process that leads to gene amplification in drug-treated mammalian cells.

Animals↗

PubMed1989

Therapy of the myeloid blast phase of chronic granulocytic leukemia with plicamycin and hydroxyurea.

Treatment of the myeloid blast phase of chronic granulocytic leukemia is still a major problem in clinical hematology. Alternate-day plicamycin and hydroxyurea treatment was reported to induce remissions in the majority of patients with myeloid blast phase by Koller and Miller in 1986 Subsequently we treated eight patients according to this regimen. Complete remissions could not be achieved and no prolongation of median survival was observed. In two patients treatment had to be discontinued due to severe toxicity.

Adult↗

PubMed1989

Induction chemotherapy with cisplatinum, 5-fluorouracil, bleomycin, mitomycin C and hydroxyurea for previously untreated locally advanced squamous cell carcinomas of the head and neck.

Fifty-three patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) were treated with a combined modality treatment consisting of three cycles of induction chemotherapy before definitive surgery and/or radiotherapy. Two additional cycles of the same chemotherapy were given after local-regional therapy. The chemotherapeutic regimen included cisplatinum 100 mg/m2 on day 1, 5-fluorouracil 1000 mg/m2 as a continuous infusion on days 2-6, bleomycin 15 units i.m. on days 15 and 29, mitomycin C 4 mg/m2 i.v. on day 22 and hydroxyurea 1000 mg/m2 p.o. on days 23-27. Each cycle was repeated every 42 days. Forty-nine patients are evaluable for response. There were 37 men and 12 women, with a median age of 58 years (range 18-75 years) and performance status of 80 (range 40-90). Sixteen patients (33%) demonstrated a complete response, 20 (41%) a partial response, yielding a 74% response rate to induction chemotherapy; 12 (24%) patients had stable disease and 1 (2%) progressive disease. The actuarial survival of those patients who completed the whole treatment program was 65% at 2 years and 47% at 3 years. Toxicities included nausea and vomiting (66%). anemia (34%), leukocytopenia (54%), thrombocytopenia (22%), stomatitis (36%), diarrhea (10%), alopecia (78%), hear impairment (4%) and transient creatinine elevation (2%). The results of the present study showed that induction chemotherapy with the above regimen produced a high rate of complete responses and can be safely combined with local-regional therapy to improve local tumor control and increase disease-free survival in patients with locally advanced SCCHN.

Adolescent↗

PubMed1992

5-Fluorouracil, leucovorin, hydroxyurea, and escalating doses of continuous-infusion cisplatin with concomitant radiotherapy: a clinical and pharmacologic study.

Cisplatin (CDDP), 5-fluorouracil (5-FU), and hydroxyurea (HU) have individually demonstrated activity against several solid tumors, act synergistically with each other in vitro, and may act as radiation sensitizers. Therefore, we designed a phase I study to determine the maximally tolerated dose of cisplatin as given in addition to our previously described combination of 5-FU, HU, and concomitant radiotherapy (XRT). Patients exhibiting advanced solid tumors requiring palliative XRT were eligible. The regimen consisted of 1 g HU given p.o.b.i.d. on days 1-5, 600 mg/m2 5-FU given i.v. daily by continuous infusion (c.i.) on days 1-5, escalating doses of cisplatin starting at 10 mg/m2 daily given by c.i. on days 1-5, and involved-field XRT carried out on days 1-5. The cycle was repeated every 14 days until the target XRT dose had been reached. In all, 19 patients were entered at the first dose level, and cumulative grade 3-4 myelosuppression was seen in 16 subjects. As no dose escalation was feasible, the chemotherapy was subsequently altered by using the above regimen for cycles 1, 3, 5, and 7 and substituting the less myelosuppressive regimen of 1 g HU given p.o.b.i.d. on days 1-5, 400 mg/m2 5-FU given i.v. daily by c.i., and 100 mg leucovorin given p.o.4 h on days 1-5 for cycles 2, 4, and 6. On this alternating program, 28 patients were treated with escalating doses of CDDP. The dose-limiting toxicity was again myelosuppression, which was prohibitive at a CDDP dose of 20 mg/m2 daily. In the final phase of the protocol, 30 subjects were treated with the above alternating-cycle regimen at a CDDP dose of 20 mg/m2 daily and a decreased HU dose of 500 mg p.o.b.i.d. in an attempt to circumvent the myelosuppression associated with this dose of CDDP. Although severe acute toxicity (cycles 1 and 2) was observed less frequently, cumulative toxicity (all cycles) remained pronounced. The other major toxicity encountered was mucositis, which was particularly pronounced in patients receiving radiation to the head and neck and following leucovorin-containing cycles. Plasma concentrations of free platinum did not correlate with the CDDP dose, possibly due to the narrow range of doses given. Pharmacodynamic modeling demonstrated that the CDDP dose and the HU dose were associated with leukopenia. Antitumor activity was demonstrated in a number of solid tumors particularly non-small-cell lung cancer and head and neck cancer.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗

PubMed1987

Hydroxyurea synchronization increases mitotic yield in human glioma cell lines.

Karyotypic studies of human gliomas are often limited by a low mitotic index and the appearance of contracted chromosomes that do not exhibit clear banding patterns. The purpose of this study was to investigate the use of hydroxyurea (HU) as a synchronizing agent using established human glioma cell lines as a model system. HU was shown to reversibly inhibit cellular replication in glioma cell lines U-251MG, D-245MG, D-247MG and D-263MG by flow cytometry on the basis of DNA content. Two-to sixfold increases were demonstrated in the mitotic index of HU-treated cultures exhibiting the greatest percentage of cells in the G2/M phases of the cell cycle. HU, therefore, promises to be an effective agent for use in short term cultures from biopsied human tumors to increase the quality of chromosome preparations in these tumors.

Cell Cycle↗

PubMed1990

Cisplatin preceded by concurrent cytarabine and hydroxyurea: a pilot study based on an in vitro model.

As previously reported, cytotoxic synergy is produced when clinically achievable concentrations of cytarabine (Ara-C) and hydroxyurea (HU) are used as potential inhibitors of in vitro DNA repair in cisplatin (cis-Pt)-treated human colon carcinoma cells. This pilot study was subsequently designed to duplicate the in vitro dose and schedule and to determine the toxicity of this three-drug combination in two cohorts of patients. 21 patients had received prior chemotherapy and 19 were not previously treated. All patients had refractory solid tumors. They received monthly cycles of an oral loading dose of 800 mg/m2 HU followed every 2 h by 6 oral doses of 400 mg/m2, a 12-h continuous infusion of 200 or 250 mg/m2/h Ara-C concurrent with the HU, and then 100 mg/m2 cis-Pt over 1 h. A total of 95 cycles were given with the expected toxicities of nausea and vomiting and fatigue but not major acute toxicity observed. Thrombocytopenia was significant but transient and was dose-limiting only for patients who had received prior therapy. The median platelet nadir after one cycle was 43,000/microliters for all patients and 67,000/microliters for those who had not undergone prior treatment. Azotemia was treatment-limiting in responding and stable patients, suggesting the possibility of synergistic nephrotoxicity. Interestingly, there were early transient rises in both uric acid and lactate dehydrogenase (LDH). Partial responses were seen in 9 of 32 patients with measurable disease and there was significantly improvement in 5 of 8 patients with only evaluable disease. The responses or improvement occurred in patients with non-small-cell lung cancer, breast carcinoma, glioblastoma, ovarian carcinoma, small-cell lung cancer, and mesothelioma. Of these 14 patients, 9 had failed prior chemotherapy regimens. Significantly, responses were observed in 3 of 8 patients who had previously received cis-Pt, suggesting that the HU/Ara-C combination modulated cis-Pt resistance. Because of these encouraging results, a second pilot study has been initiated with modifications dictated by the toxicity issues raised in this trial.

Adult↗

PubMed1989

Phase II trial of plicamycin and hydroxyurea in acute myelogenous leukemia.

A total of 23 patients with high-risk acute myelogenous leukemia (AML) at diagnosis (2 patients), relapsing AML (14) or resistant AML (6) were treated with 25 micrograms/kg i.v. plicamycin every other day for 3 weeks and 500-4,000 mg hydroxyurea per day p. o. according to the WBC count. Aplasia was observed in only two patients. Severe extrahematologic toxicity included sepsis (four cases), vomiting (four patients), toxic hepatitis (three cases), and fibrinopenia (one patient). No partial or complete responses were observed. The 95% confidence interval limit of the overall response rate (CR + PR) was 0-14%.

Bone Marrow↗

PubMed1981

Effect of hydroxyurea on two different types of hematopoietic stem cells (CFU-S and DCPC) of newborn mice.

Pluripotent hematopoietic stem cells from the bone marrow of newborn mice (9--13 days of age) have been studied following the administration of hydroxyurea (HU, 1,000 mg/kg). Following a single injection as well as a regimen of eight injections complete bone marrow reconstitution was achieved after 7 days. During the recovery phase diffusion chamber progenitor cells (DCPC) from pretreated newborn mouse bone marrow proliferated strongly to give significantly higher cell yields than DCPC from control animals. By contrast (colony-forming units-spleen [CFU-S]) levels were reduced at the same time to between 15 and 40% of controls suggesting a small-sized reserve pool of resting CFU-S in newborn mice. Assuming that DCPC are less differentiated than CFU-S and are non-cycling stem cells they may possibly pass through the CFU-S stage rapidly in newborn mice under the stress of hematopoietic reconstitution and proceed directly to myelopoiesis.

Animals↗

PubMed1993

Pilot study of 6 weeks of chemoradiotherapy with 5 FU and hydroxyurea in malignant gliomas.

In an attempt to improve the primary treatment of malignant gliomas we used a concomitant 6-week course of chemoradiotherapy with 5 fluorouracil (5 FU) and hydroxyurea (HU) in 24 adults with anaplastic astrocytoma (AA) (7 cases) or glioblastomas (GLB) (17 cases). This patient population was characterised by a poor prognostic profile; 50% of cases had biopsic or subtotal surgery and 70% had GLB. Patients received 2 Gy/day 18 MV photons with 300 mg/m2 of 5 FU in continuous infusion and 500 mg x 4/day per os of HU, five days per week during 6 weeks. Treatment was poorly tolerated in terms of toxicity and implied heavy logistics (hospitalization, central venous access) worsening the quality of life which is already bad in malignant gliomas. Unfortunately we did not improve median survival which does not exceed 26 weeks with 7 long survivors (> 49 weeks). This pilot study does not offer any benefits over current standard approaches. Aggressive locoregional approaches such as this should perhaps be attempted in patients with a better profile.

Adult↗

PubMed1979

[Influence of hydroxyurea on DNA synthesis of human bone marrow in vivo (author's transl)].

Four patients, who suffered from malignant, disseminated tumors but had a morphologically intact bone marrow, where given a peroral Hydroxyurea (HU) infusion in a concentration of about 5 x 10(-4) mol over a period of 10 h. As indicator of the DNA synthesis the 3H-TdR-incorporation of bone marrow, gained by puncture before, during, and/or after HU application, was measured. While using HU, the DNA synthesis was extensively inhibited. Fourteen to 16 h after discontinuing the HU it increased by the factor 1.5 to 2 of the initial value, i.e., before treatment. This is interpreted as a partial synchronization of bone marrow cells where effects of cell depletion and recruitment are not to be entirely excluded, Toxicity, such as the decrease of peripheral blood cells or nausea, did not occur.

Adult↗

PubMed1981

Bromodeoxyuridine mutagenesis, ribonucleotide reductase activity, and deoxyribonucleotide pools in hydroxyurea-resistant mutants.

Ribonucleotide reductase activity and deoxyribonucleoside triphosphate (dNTP) pools were examined in several Syrian hamster melanoma cell mutants which are resistant to hydroxyurea (HU), an inhibitor of ribonucleotide reductase, and which also show increased resistance to bromdeoxyuridine (BrdU) mutagenesis. For most of the mutants, resistance to HU and BrdU mutagenesis is associated with increased levels of ribonucleotide reductase activity. No evidence was found for qualitative alterations in the ribonucleotide reductase in the mutant cells. The dNTP pools in the mutants are somewhat resistant to the perturbations can be produced in wild-type cells by the addition of BrdU, although significant perturbations can be produced in the mutants by higher concentrations of BrdU. The decrease in BrdU-induced nucleotide pool perturbations may account for the resistance of the mutants to BrdU mutagenesis.

Animals↗

PubMed1979

Resistance to bromodeoxyuridine mutagenesis and toxicity in mammalian cells selected for resistance to hydroxyurea.

Mutant cell lines resistant to hydroxyurea (HU), an inhibitor of the enzyme ribonucleotide reductase, were selected from a line of Syrian hamster melanoma cells. Mutant lines were selected for resistance to 0.3 mM HU, and from these lines, second-step mutants were selected for resistance to 1.9 mM HU. The HUr lines were tested ffor their responses to 5-bromodeoxyuridine (brdU), in terms of toxicity, mutagenesis, and incorporation of BrdU into DNA. All of the HUr lines showed increased resistance to the toxic effects of BrdU. in addition, the HUr lines all were resistant to BrdU mutagenesis. Overall, there was good correlation among the levels of resistance to HU toxicity, BrdU toxicity, and BrdU mutagenesis in the HUr lines. These tests were carried out under conditions such that the parental and HUr cells incorporated equal amounts of BrdU into nuclear DNA. Therefore, the resistance of the HUr cells to the effects of BrdU cannot be attributed to decreased incorporation of BrdU into DNA. These results suggest that the HUr cells have an lateration in ribonucleotide reductase activity that simultaneously confers resistance to HU and BrdU. The properties of the HUr cells suggest that the perturbation of deoxcytidine metabolism by BrdU. The properties of the HUr cells suggest that the perturbation of deoxcytidine metabolism by BrdU triphosphate inhibition of ribonucleotide reductase activity plays a key role in the toxic and mutagenic effects of BrdU in mammalian cells.

Animals↗

PubMed1995

Circulating hematopoietic progenitor cells in polycythemia vera: the in vivo effect of hydroxyurea.

The in vivo effects of hydroxyurea (HU) on circulating erythroid (BFU-E) and granulocyte-macrophage progenitors (CFU-GM) in patients with polycythemia vera (PV) have been evaluated. HU induced a strong decrease of both BFU-E and CFU-GM in the first month of treatment. During the following 4 months of treatment the level of circulating progenitors remained at very low values, until the end of the period of observation. HU activity involved both erythroid and myeloid committed progenitors and both erythropoietin-stimulated (normal) and endogenous (derived from the abnormal PV clone) BFU-E.

Aged↗