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PubMed1979

Cell cycle synchronization of the mouse S-180 tumor following alternating period of hydroxyurea-blockade and release.

An attempt at synchronization was carried out by intravenous administration of hydroxyurea (HU) into mice bearing the S-180 solid tumor. Following HU blockade for 6.0 hrs equal to (Tc-Ts) period, 65% of all tumor cells were in S-phase. After 2 cycle blockade; HU blockade for 6 hrs, released for 7.5 hrs and reestablished for 6 hrs, 84% of tumor cells were gathered in S-phase with a sharp peak at G1-S junction. Appropriate cycles of HU infusion and release will synchronize significant increments of S-phase or mitotic cells in the S-180 tumor during predictable time intervals.

Animals↗

PubMed1979

Erythroid stem cell regeneration in normal and plethoric mice treated with hydroxyurea.

Hydroxyurea (4 x 500 mg/kg at 6 hour intervals) was used to study hemopoietic regeneration in normal and in hypertransfused mice. All recognizable granuloid and erythroid cells, most granulopoietic (CFU-C) and all erythroid (CFU-E) precursors and about 80% of the pluripotent stem cells were eliminated after this treatment. Regeneration started between days 2 and 3 in the marrow and 1 day later in the spleen. An overshoot in CFU-C and CFU-E per femur was seen at day 4. In parallel to their committed precursors granulopoietic cells reappeared between days 2 and 4, erythroblasts between days 3 and 5. In the spleen a maximum CFU-S and CFU-C concentration was seen at day 7. The early increase of CFU-E in the marrow was followed by a fall to low levels, then the CFU-E concentration in the spleen increased. The regeneration was further studied in hypertransfused mice. CFU-S and also CFU-E in the marrow regenerated in exactly the same way as in normal mice and erythroblasts were found in marrow smears. The further maturation of erythroblasts to reticulocytes was impaired in hypertransfused mice, but not in normal mice. The role of erythropoietin (Ep) in the regulation of the CFU-E regeneration is discussed; early differentiation steps seem to be possible without Ep.

Animals↗

PubMed1980

Phase I study using combination of hydroxyurea and 5-azacytidine (NSC-102816).

Thirteen patients were treated with a hydroxyurea -- 5-azacytidine combination in an attempt to show an increase in therapeutic efficacy of 5-azacytidine without increased bone marrow toxicity. Leukemic and nonleukemic patients were selected in order to compare the effect of a combination therapy on bone marrow. There was no clear-cut tumor response observed in evaluable patients. Overall activity of the combination, as judged by the onset of myelosuppression, appears to be higher than that of 5-azacytidine given alone.

Adult↗

PubMed1983

Biochemical and cytokinetic modulation of L1210 and HL-60 cells by hydroxyurea and effect on 1-beta-D-arabinofuranosylcytosine metabolism and cytotoxicity.

The modulating effect of hydroxyurea (HU) on 1-beta-D-arabinofuranosylcytosine (ara-C) metabolism and cytotoxicity was evaluated in L1210 cells and the human promyelocytic leukemic cells HL-60. A dose- and time-dependent HU exposure was observed which resulted in maximum deoxycytidine 5'-triphosphate reduction, intracellular ara-C accumulation, 1-beta-D-arabinofuranosylcytosine 5'-triphosphate formation, and cytotoxicity as determined by soft agar cloning. For the L1210 cells, a 5-hr pretreatment of 5 mM HU was optimum. The best result obtained with the HL-60 cells was after a 24-hr exposure of 1 mM HU. There was also a maximum incorporation of ara-C into DNA in both cells following these optimal pretreatment conditions. Cytofluorometric analysis demonstrated that this HU treatment resulted in a maximum accumulation of L1210 and HL-60 cells in the pre-S phase of the cell cycle and that after removal of the HU there was a rapid progression of the cell population through S phase. Because cytotoxicity of ara-C is considered to be predominantly from the inhibition of DNA polymerase and/or the incorporation into DNA, the cytokinetic and biochemical modulatory effects of HU must both be contributing factors to consider in achieving maximal cell kill from this drug sequence.

Animals↗

PubMed1983

Alteration in lysosome supravital staining as a marker of hydroxyurea-induced cytotoxicity and its modification by radical scavengers in L5178Y cells in culture.

Supravital staining of lysosomal membranes with euchrysine was employed to study hydroxyurea (HU)-induced side toxic effects in L5178Y lymphoblasts in culture. Exposure of cells to 0.1-1.0-10.0 mM HU-induced progressive increase in the proportion of cells without detectable lysosomal fluorescence. This effect preceded the occurrence of non-viable cells, determined by trypan-blue exclusion test. Addition of alpha-tocopherol, acetylsalicylic acid, sodium benzoate or ascorbic acid to the culture medium afforded a concentration-dependent modification of lysosomal response to HU treatment. It is suggested that the fluorescence technique of supravital lysosome staining can be a useful test in studies on the side toxic effects of free radical-forming drugs and their amelioration by radical scavengers.

Animals↗

PubMed1984

Enhancement of the DNA breakage and cytotoxic effects of intercalating agents by treatment with sublethal doses of 1-beta-D-arabinofuranosylcytosine or hydroxyurea in L1210 cells.

4'-(9-Acridinylamino)methanesulfon-m-anisidide (m-AMSA) and other DNA intercalating agents produce protein-associated DNA strand breaks, the formation of which are mediated by topoisomerase-like chromosomal proteins. As topoisomerases would be expected to be most active during DNA replication, DNA synthesis inhibitors may alter the sensitivity of cellular DNA to intercalator-induced scission. We report that treatment of L1210 cells with 1-beta-D-arabinofuranosylcytosine (ara-C) (0.1 microM) or hydroxyurea (HU) (0.1 mM) for 18 hr resulted in a 2- to 2.4-fold enhancement of m-AMSA-induced protein-associated DNA single-strand breaks and DNA-protein cross-links as measured by alkaline elution. This enhancement was dependent on the duration of ara-C or HU treatment as well as on the concentration of ara-C or HU. Enhancement did not correlate with any alteration in cellular uptake of intercalator or with ara-C- or HU-induced alterations in the DNA synthetic rate. The DNA within nuclei isolated from ara-C- or HU-treated cells also displayed an enhanced susceptibility to m-AMSA-induced scission. There was a correlation between enhanced single-strand break formation and recruitment of cells into S-phase as well as between single-strand break formation and the production of a hypomethylated state of cellular DNA. Concurrent with the enhancement of m-AMSA-induced cellular DNA effects was a synergistic effect on m-AMSA cytotoxicity by ara-C or HU. This enhancement of intercalator effects was also found for the intercalator Adriamycin. We propose that these sublethal concentrations of ara-C and HU alter chromatin structure possibly via DNA hypomethylation and/or altered DNA-histone interactions so that intercalator-induced DNA effects are enhanced. Alternatively, the topoisomerase-like activity involved in intercalator-induced, protein-associated DNA break production may be increased in the nuclei of ara-C- or HU-treated cells.

Aminoacridines↗

PubMed1984

Chemotherapy of advanced colorectal carcinoma: fluorouracil alone vs. two drug combinations using fluorouracil, hydroxyurea, semustine, dacarbazine, razoxane, and mitomycin. A phase III trial by the Eastern Cooperative Oncology Group (EST: 1278).

Patients with advanced colorectal cancer and no prior chemotherapy were randomized to six treatment regimens: A) fluorouracil (FU) alone; B) FU + hydroxyurea (HU); C) semustine (SE) + dacarbazine (DA); D) FU + HU alternating with SE + DA; E) SE + razoxane (RA); F) mitomycin (MI) + DA. There were no significant treatment differences with respect to response, which ranged from 9-23% (overall 32/207 or 15%) or median survival duration, which ranged from 17 weeks to 32 weeks. Patients treated with FU or FU + HU experienced substantially less toxicity than those on the other treatment arms.

Adenocarcinoma↗

PubMed1984

Evaluation of a sequential 5-FU and hydroxyurea combination in advanced bowel cancer.

Twenty-nine patients (two with small bowel cancer and 27 with colorectal cancer) were treated with a sequential 5-FU-hydroxyurea combination following the suggestion of schedule-dependent synergism in experimental systems. No enhanced toxicity was observed, but the response rate was only 4%. Seven additional patients manifested greater than or equal to 50% declines in CEA, but caution must be used in interpreting such changes as antitumor activity.

Adult↗

PubMed1983

Phase I trial of cytarabine and hydroxyurea.

A combination of hydroxyurea (HU) and cytarabine (ara-C) can overcome ara-C resistance in vitro. To determine the pattern of toxicity of this combination, 22 patients with refractory leukemia and lymphoma were treated for 5 days with ara-C (100 mg/m2/day by constant infusion) and escalating doses of HU (0.375-1.77 g/m2 every 6 hours). Hematologic toxicity was severe even at the lowest HU dose level. Skin and mucosal toxic effects were frequent but not dose-limiting. No novel types of toxic effects were observed.

Adolescent↗

PubMed1983

Management of infected stone disease with hydroxyurea: a five year follow-up.

Hydroxyurea in a morning dose of 500 mg along with Macrodantin, 100 mg, has been used for more than five years as an adjunct to the management of retained struvite stones. Mild reversible toxicity occurs in 10 per cent. Urine sterility can be achieved in ninety per cent and no growth of the retained stone occurs.

Humans↗

PubMed1983

An electron microscopic study of early reversible hydroxyurea cataracts in vitro.

The crystalline lenses of male white Wistar rats weighing 100 gr. were cultured in a culture fluid containing 5 X 10(-2) M hydroxyurea. The epithelial cells forming multiple layers in the equatorial region on the 4th day of incubation and swollen epithelial cells were studied by electron microscopy and the results are summarized as follows; The epithelial cells forming multiple layers retained a desmosome-like structure near the apical region. It was assumed that these cells preserve their epithelial properties. The cellular morphology and subcellular organela had the characteristics of epithelial cells. The scarcity of microtubules in the epithelial multiple layers was interpreted as reduced capacity of these cells for elongation.

Animals↗

PubMed1984

[Relation of the survival of mouse hematopoietic stem cells to the interval between periodic injections of hydroxyurea].

The dependence was studied between the survival of proliferating hemopoietic stem cells (CFUs) on the interval between regular multiple injections of hydroxyurea (HU). Before HU injection mice were irradiated in a dose of 200 rad to trigger the proliferation of CFUs. The dependence obtained is resonance in character, with a maximum being attained during injections made with a 12-hour interval. Comparison with the mathematical model indicates that interval corresponding with the maximal survival should correlate with the mean time of the generation of proliferating CFUs.

Animals↗

PubMed1978

Chemo-hormonal therapy for metastatic renal cell carcinoma with adriamycin, hydroxyurea, vinblastine, and medroxyprogesterone acetate.

In a phase II study, eight patients with metastatic renal cell carcinoma have been treated with a combination of chemotherapy and hormonal therapy using adriamycin, hydroxyurea, vinblastine, and medroxyprogesterone acetate. Five patients have responded, including one with complete response, one with subjective improvement, and three with partial responses. The median survival was 4 months with a range of 4--11 months. With the exception of mild alopecia and nausea, toxicity was minimal; no significant hematologic toxicity was noted. The initial results of this study suggest that chemo-hormonal therapy plays a significant role in the management of renal cell carcinoma.

Adenocarcinoma↗

PubMed1980

Hydroxyurea as a reference standard in teratological screening. Comparison of the embryotoxic and teratogenic effects following single intraperitoneal or repeated oral administrations to pregnant rats.

The antimitotic drug hydroxyurea (HU) has been evaluated as a positive standard for teratological screening in rats. Single intraperitoneal administration of HU to pregnant Sprague Dawley rats at the dose level of 750 mg/kg induced embryolethality or specific anomalies depending on the day of treatment: HU administration on days 7, 8, 9, 10 or 11 produced lethal effects in a high percentage of embryos; cardiovascular malformations were specifically induced by a single dose on day 10, ocular anomalies on day 10 or 11, palatoschisis or diaphragmatic hernia on day 12, limb or paw deformities on day 10, 11, 12 or 13. This experiment demonstrated the high susceptibility of the genotype of our colony of rats to the embryotoxic potential of HU. Repeated oral administration of HU during the organogenetic period (from day 6 to day 15 of gestation), at dose levels ranging from 50 to 450 mg/kg, led to a dose dependent embryolethal and teratogenic effect. Live foetuses at term generally showed severe ocular and craniofacial anomalies; hydrocephalus, cardiovascular anomalies, vertebral and costal defects were also registered. Limb malformations were not frequent and paw abnormalities were totally absent. In our experimental conditions, the dose level of 300 mg/kg is regarded as a suitable positive control dosage in teratological testing of new molecules by oral route.

Abnormalities, Drug-Induced↗

PubMed1980

The use of hydroxyurea to study the proliferative state of T-cell precursors (CFUT) in murine bone marrow.

The cycle specific drug, hydroxyurea (HU), has previously been used to study the proliferative kinetics of various hemopoietic precursor cells such as granulocyte-macrophage precursors (CFUc) and multipotential stem cells (CFUs). We have investigated the kinetics of another hemopoietic precursor, a T-cell colony (CFUT). When mice are exposed to two doses of HU, separated by 7 h, CFUT are reduced to approximately 30% of the control value. Surviving cells in the bone marrow quickly replenish the population and return it to normal values 2 days after HU treatment. When fresh bone marrow cells or bone marrow cells harvested from mice exposed 24 h earlier to HU are treated in vitro with HU, CFUT activity is reduced by approximately 70%. These data indicate that CFUT is a rapidly proliferating population with a large proportion of the cells always in cell cycle.

Animals↗

PubMed1980

[Irradiation of solid Walker carcino-sarcomas after synchronisation with hydroxyurea (author's transl)].

Sprague-Dawley rats with solid Walker carcino-sarcomas were synchronized with hydroxyurea (HU; 6 x 50 mg and 1 x 300 mg HU/kg body weight) and then irradiated at different time points (60Co). The synchronized tumors showed a significant delay of growth when irradiation was applied in the late G1 phase, at the transition G1/S and in the early S phase. The remaining phases of the cell cycle, especially the S phase showed the same sensitivity as the non-synchronized controls. Improvement of therapy by irradiation after HU application was largely due to the synchronization of tumor cells. Only the increased therapeutic effect of irradiation shortly after application of HU can be explained also by combination of both HU and irradiation.

Animals↗

PubMed1982

Diagnosis of canine primary polycythemia and management with hydroxyurea.

Severe polycythemia was found in 3 dogs with PCV 68% to 70%. Direct RBC mass determinations were increased in all dogs, confirming absolute polycythemia. Cause for secondary polycythemia was not found in any of the dogs; serum erythropoietin concentrations were undetectable, consistent with primary polycythemia. The polycythemia and associated clinical signs were controlled successfully for extended periods (mean, 16.6 months), using phlebotomy followed by oral administration of hydroxyurea in loading and in daily maintenance dosages.

Animals↗

PubMed1982

The influence of colchicine on the cytotoxic effect of hydroxyurea in the embryonic spinal cord of the mouse.

The development of necroses and the course of the mitotic index in the embryonic spinal cord of 10-day-old mouse embryos (NMRI) were investigated between 1.5 h and 4 h after either an intraperitoneal application of 500 mg/kg hydroxyurea (HU) or 1 mg/kg colchicine or a simultaneous application of both substances. One h and 30 min after colchicine application, the mitotic index of the neuroepithelial cells had decreased (5.22%; control 7.7%). Subsequently, the mitotic index increased, reaching a maximum of 10.35% 2 h and 30 min after colchicine application. Between 1 h and 30 min and 4 h after HU application, the mitotic index decreased from 4.6% to 0.61% (control 7.7%). First necroses of neuroepithelial cells were observed 1 h and 50 min after HU application. 4 h after HU treatment, 34.38% of the neuroepithelial cells were necrotic. After simultaneous application of HU and colchicine, the decrease of the mitotic index was similar to the decrease after HU application alone. No necroses were observed in the embryonic spinal cord during a 4 h period after simultaneous application of HU and colchicine. After colchicine, as well as after simultaneous HU and colchicine application, the shape of the nuclei of the neuroepithelial cells changed from oval to round and the chromatin was condensed. Mechanisms for the inhibition of the cytotoxic but not the cytokinetic effects of HU by colchicine are discussed.

Animals↗