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PubMed1991

Comparison of the effect of hydroxyurea and methotrexate on DNA fragmentation at various reaction conditions.

Using the changes in DNA breakage as a marker of DNA damage, the direct action of hydroxyurea (HU) and methotrexate (MTX) on DNA was examined. The experimental design was to expose isolated DNA to HU and MTX alone or HU and MTX with accelerators of free radical reaction (H2O2, Fe..) and to determine DNA fragmentation assessed by electrophoresis. The results indicated that HU can damage DNA, but to demonstrate this ability it needs H2O2, Fe.. or prolonged incubation in solution. Unlike HU, MTX with H2O2 was ineffective; MTX with Fe.. at certain degree protected DNA against lesions induced by Fe.. alone. It is concluded that despite several common features of HU- and MTX-induced toxic side-effects in the cells suggesting interference of these drugs with free radical reactions, their direct effect on DNA under oxidizing conditions is quite different at least at the concentrations used by us.

DNA↗

PubMed1991

Effects of thymidine and hydroxyurea on the metabolism and cytotoxicity of 1-B-D arabinofuranosylcytosine in highly resistant human leukemia cells.

We have examined the effect of the ribonucleotide reductase inhibitors thymidine (dThd) and hydroxyurea (HU) on the metabolism and cytotoxicity of high concentrations (10 to 100 mumol/L) of cytosine arabinoside (Ara-C) in a deoxycytidine kinase-deficient, highly Ara-C-resistant human promyelocytic leukemic cell subline (HL-60/Ara-C). Administration of dThd or HU (0.5 to 3 mmol/L) in conjunction with high concentrations of Ara-C either sequentially or simultaneously lead to enhanced (and in some cases a supra-additive) inhibition of HL-60/Ara-C suspension culture growth and soft agar colony formation. In addition, exposure of cells to 0.5 mmol/L dThd or HU for 48 hours significantly increased the percentage of HL-60/Ara-C in S-phase. In contrast to previous studies involving low-dose Ara-C administration, we were unable to detect dThd- or HU-mediated increments in Ara-CTP formation in HL-60/Ara-C cells treated with high-dose Ara-C despite reductions in intracellular dCTP pools as great as 65%. However, dThd or HU did increase Ara-C incorporation into newly synthesized DNA. These studies show that administration of dThd or HU in conjunction with high concentrations of Ara-C results in an enhanced antiproliferative effect of Ara-C against Ara-C-resistant leukemic cells deficient in deoxycytidine kinase.

Arabinofuranosylcytosine Triphosphate↗

PubMed1991

Inhibition of cis-diammine-1,1-cyclobutane dicarboxylatoplatinum(II)-induced DNA interstand cross-link removal and potentiation of cis-diammine-1,1-cyclobutane dicarboxylatoplatinum(II) cytotoxicity by hydroxyurea and 1-beta-D-arabinofuranosylcytosine.

1-beta-D-Arabinofuranosylcytosine (ara-C) and hydroxyurea (HU) were investigated as potential DNA repair inhibitors with cis-diammine-1,1-cyclobutane dicarboxylatoplatinum(II) (CBDCA). HU plus ara-C, known inhibitors of DNA excision-repair, had previously been found to produce cytotoxic synergy and delayed removal of DNA interstrand cross-links with cis-diamminedichloroplatinum(II) (DDP). Since CBDCA and DDP share a common active intermediate, it should be possible to reproduce this interaction with CBDCA. However, the stable dicarboxylate chelate ring structure of CBDCA results in kinetics that differ significantly from those of DDP, due to slower hydrolysis to the active species. DNA adducts form more slowly, with interstand cross-links peaking approximately 12-h later and disappearing more gradually than in the case of DDP. It was therefore expected that a longer antimetabolite exposure might be required for repair inhibition with CBDCA. The 12-h exposure to HU plus ara-C previously found effective with DDP produced no cytotoxic synergy with a 2-h CBDCA exposure. Lengthening the antimetabolite treatment to 24 h resulted in approximately 1 log of synergistic toxicity, while a 24-h simultaneous exposure to HU, ara-C, and CBDCA resulted in 2 logs. Cells exposed to all three drugs showed a 2- to 3-fold greater level of interstrand cross-links after 36- to 48-h of incubation following drug removal, compared to CBDCA alone. Taken together, these findings suggest that HU plus ara-C modulates the repair of platinum-DNA adducts and establishes an effective in vitro schedule at clinically achievable concentrations for the use of those antimetabolites with CBDCA.

Animals↗

PubMed1991

Genetic destabilization of Candida albicans by hydroxyurea.

Candida albicans is a commensal component of the normal human microflora, but frequently causes infections in persons undergoing treatment for malignancies. The cytotoxicity and genotoxicity of the antineoplastic agent hydroxyurea (HU) for the yeast is demonstrated. Cultivation of the organism on defined complete medium in the presence of HU induced growth inhibition or cell death, gene mutations, segregations of heterozygous loci through reciprocal and nonreciprocal mitotic recombinations, and a special heritable system for high frequency switching between phenotypes reflecting cellular growth characteristics and susceptibilities to HU. Each of these responses is influenced differently by variations in drug concentration and temperature. The biochemical complexity underlying cytotoxic and genetic effects of HU, and the implications for the likelihood of HU induced changes occurring in indigenous yeast populations of persons undergoing therapy with the drug, are discussed.

Candida albicans↗

PubMedDate not supplied

The plicamycin and hydroxyurea combination chemotherapy for chronic granulocytic leukemia in myeloid transformation.

Between 1987-1988 we treated, in a cooperative study, 13 patients in blast crisis of CGL according to Koller and Miller's regimen. We observed no return to the chronic phase of the disease, while some patients suffered major drug-induced side effects. Six patients in accelerated phase were treated with the same combination therapy. All of them responded with a return to the chronic phase for a median of 4.5 months. In our hands the combination of plicamycin and hydroxyurea was ineffective in patients with CGL in blast crisis. This regimen could deserve further evaluation in patients with CGL in acceleration.

Adult↗

PubMed1975

Synergic action of distamycin A and hydroxyurea on the reproduction of DNA viruses in cell cultures.

The antiviral activity of the combination of distamycin A (DA) Pand hydroxyurea (HU) on the reproduction of vaccinia and pseudorabies viruses was investigated. The drug combination exerted a significant synergic inhibitory effect on the vaccinia virus yield and on the plaque formation in chick embryo cells. Similar experiments on pseudorabies virus showed an additive effect. The possible mechanism of the mutual enhancement of the antiviral activity is discussed.

Amidines↗

PubMed1986

Hydroxyurea induction of hemoglobin F production in sickle cell disease: relationship between cytotoxicity and F cell production.

Initial alterations in fetal hemoglobin (HbF) production among eight sickle cell anemia subjects treated with hydroxyurea (Hu) are summarized. Four of these subjects had been previously treated with 5-azacytidine (5-aza). All subjects treated with Hu (50 mg/kg/d for three to five days) had suppression of their total reticulocyte counts by seven days, whereas the four subjects previously treated with 5-aza (2 mg/kg/d for three to five days) had increased reticulocyte counts at day 7. The effect of Hu on increasing the number of HbF-containing reticulocytes (F reticulocytes) is extremely variable, ranging from ten-to less than onefold differences in maximal posttherapy v pretherapy levels. Recovery from marrow suppression did not result in greater than twofold increases in F reticulocyte counts. Mean day 7 F reticulocyte levels in the four subjects treated with both Hu and 5-aza were 4.1 X 10/microL and 15.4 X 10(4)/microL, respectively. Among Hu-treated subjects, increased F reticulocyte production was correlated with low serum creatinine levels and rapid removal of Hu from the plasma. Furthermore, suppression of CFU-E colony formation on day 2 of therapy with Hu was inversely correlated with maximal F reticulocyte response. We conclude that where Hu treatment results in marrow toxicity (decreased reticulocyte counts, decreased CFU-E colony formation) HbF production is less likely to increase. Those sickle cell anemia subjects with minimal renal dysfunction (serum creatinine level, greater than 1.0 mg/dL) exhibit the most cytotoxicity and least F reticulocyte response to Hu.

Anemia, Sickle Cell↗

PubMed1987

Hydroxyurea-induced augmentation of fetal hemoglobin production in patients with sickle cell anemia.

Five patients with sickle cell anemia were treated with hydroxyurea (HU), in hopes of augmenting their production of fetal hemoglobin. Laboratory responses in two patients treated for more than 2 years were encouraging and there were suggestions of clinical improvement. Long-term HU therapy should be considered for severely affected adults with sickle cell anemia who are willing to accept what is probably a small risk of carcinogenesis. Preliminary chromosomal analysis and knowledge of the clastogenic properties of HU suggest that conception and pregnancy should be avoided. Pharmacokinetic studies will probably be necessary to adjust individual dosage schedules so that cytotoxicity is avoided. F cell responses can be seen in 2 to 3 weeks if the HU dose is optimal, but establishment of a large number of F cells in the circulation may take a month or longer.

Adult↗

PubMed1988

Heritable high frequency modulation of antigen expression in neoplastic cells exposed to 5-aza-2'-deoxycytidine or hydroxyurea: analysis and implications.

A study was undertaken to determine the ability of the DNA hypomethylating drug 5-aza-2'-deoxycytidine (5-azadCyd) to induce antigen expression in a high proportion of treated tumor cells and to evaluate if this effect could be mimicked by the drug hydroxyurea (HU) which is a genomic DNA hypermethylating agent. Induction of heritable changes in gene expression by 5-azacytidine or the 2'-deoxy analogue (5-azadCyd), at least in some cases, may not be necessarily due to their hypomethylating properties, but to some other induced high frequency genetic change which occurs when DNA synthesis or repair is perturbed. A comparison of 5-azadCyd and HU effects on human and murine tumors was chosen for this study. The phenotypic properties examined with the above treatments were (a) induction of a Mr 110,000 antigen, detected with M111 antibody, in a variant subpopulation (SMeLus7) of human melanoma cells which fail to maximally express this antigen (M111). The parent cell line, MeWo, and other MeWo-derived variant cell cell lines do not demonstrate a similarly inducible phenotype; and (b) induction of class I major histocompatibility complex antigens in a population of mouse mammary adenocarcinoma cells which normally fail to express these antigens. The results showed that 5-azadCyd was effective in inducing antigen expression in both systems whereas HU was effective (and equally so) only in the human melanoma cell line system. In these treatments 5-azadCyd was demonstrated to transiently hypomethylate the same human melanoma cell line whereas HU hypermethylated genomic cytosines. The results suggest that some of the reported effects of 5-azacytidine or 5-azadCyd in inducing very high frequency heritable phenotypic alterations may not necessarily be related to the drugs' ability to cause DNA hypomethylation. The implications of these results are discussed in terms of the use of 5-azacytidine or 5-azadCyd and the effects of chemotherapy on tumor progression and metastasis.

Animals↗

PubMed1989

[Myeloid crisis of chronic myelogenous leukemia showing dramatic response to mithramycin and hydroxyurea combination].

After 4 years of chronic phase, a 22-year-old female with Ph1 (+) chronic myelogenous leukemia developed myelomonocytic crisis. On admission, her Hb was 9.9 g/dl, Plt 4.1 x 10(4)/microliters, WBC 138,000/microliters with 16.5% blasts. Bone marrow contained 38% blasts. She received a combination chemotherapy of mithramycin and hydroxyurea, as reported by Koller et al. Dose of mithramycin was reduced to 20 micrograms/kg. Following 1st and 2nd infusions of mithramycin, severe nasal bleeding was seen. Prednisolone 10 mg/day was given from the 3rd dose of mithramycin with apparent hemostatic effects. Calcium gluconate 3 g/day was administered concomitantly. Her disease responded promptly to this treatment and hematological remission was achieved.

Adult↗

PubMed1989

A prospective randomized comparison of methotrexate, dactinomycin, and chlorambucil versus methotrexate, dactinomycin, cyclophosphamide, doxorubicin, melphalan, hydroxyurea, and vincristine in "poor prognosis" metastatic gestational trophoblastic disease: a Gynecologic Oncology Group study.

In 1981, the Gynecologic Oncology Group initiated a prospective randomized study in which patients with poor-prognosis gestational trophoblastic disease received either standard MAC chemotherapy (methotrexate, dactinomycin, and chlorambucil) or the modified CHAMOMA regimen (methotrexate, dactinomycin, cyclophosphamide, doxorubicin, melphalan, hydroxyurea, and vincristine). The protocol was closed in May 1986 because the modified CHAMOMA regimen was significantly more toxic and possibly less effective. There were 42 patients entered, with 22 receiving MAC and 20 receiving modified CHAMOMA. There have been six deaths due to disease in the modified CHAMOMA group and none in the MAC group. Five MAC failures and one modified CHAMOMA failure have been rescued by surgery and/or chemotherapy. All six of the patients who died on the modified CHAMOMA regimen had developed disease following a previous term pregnancy, but none had prior chemotherapy. All seven patients who were treated for gestational trophoblastic disease after term pregnancy in the MAC group were cured of disease. With the modified CHAMOMA regimen, 44% of patients had life-threatening hematologic toxicity, as compared with only 9% of the MAC patients. Thus, the standard MAC regimen appears to be at least equally effective and much less toxic than the modified CHAMOMA regimen, indicating a more favorable therapeutic index.

Adult↗

PubMed1989

[Apoptosis and regeneration of the gastric mucosa under the action of S-phase-specific agent, hydroxyurea].

The treatment of periodic injections of hydroxyurea to mice on the processes of regeneration in gastric mucosa was studied. In all experimental groups of animals dystrophic and atrophic changes of gastric mucosa could be observed. The phenomena of dystrophy were more pronounced. If the time of the experiment was not more than 4 days apoptosis bodies could be found only in the epithelium. The long-term duration of the experiment resulted in increased death of apoptosis bodies inside the glands, and development of atrophy of gastric mucosa.

Animals↗

PubMed1989

[Circadian rhythm of reaction of epithelial cells of the tongue and esophagus to the effects of hydroxyurea].

A study was made of the effect of a single injection of hydroxyurea (HU) on the daily rhythm of labelling index (LI) in the epithelial cells of the tongue and esophagus. HU was injected 6 times a day. The degree of decrease in the LI at varying times of the day correlated well with the initial level of the LI. At the same time the number of sensitive cells changed thought the day in a different proportion than LI rhythm, the fact suggesting the independence of these rhythms.

Animals↗

PubMed1989

Hydroxyurea-induced toxic side-effects in animals and an attempt at reducing them with vitamins E and C.

Using the changes in several blood parameters and in the histological picture of the liver as markers of toxicity, the effect of hydroxyurea (HU) in healthy rabbits or mice was examined during two weeks after a single administration of this drug. In rabbits a transient significant decrease in blood erythrocyte count with a gradual increase in their osmotic resistance, a suppression of granulocyte phagocytic capacity, and an elevation of acid phosphatase activity in the serum were found. An increase in the proportion of lymphocytes without detectable lysosomes as tested by supravital staining also appeared. No significant difference was observed in the white cell count and lipoperoxide levels after HU administration. Histological picture of the liver, excised from HU-treated mice, indicated a marked hepatotoxicity of the drug. Some of the toxic effects were reduced in animals supplemented with vitamins E and C.

Acid Phosphatase↗

PubMed1988

Induction of Epstein-Barr virus antigens by hydroxyurea.

Treatment of the Epstein-Barr virus (EBV)-transformed, virus-producer P3HR-1 cell line with hydroxyurea (HU) resulted in increased synthesis of the EBV-specific early antigen (EA) and viral capsid antigen (VCA). The induction was noted already at a 200 mumol/l and reached plateau at a 1500 mumol/l HU concentration. At plateau concentration, the percentage of cells expressing EA and VCA was about 5 times higher than in the absence of the drug.

Antigens, Viral↗

PubMed1989

1-beta-D-arabinofuranosylcytosine and hydroxyurea production of cytotoxic synergy with cis-diamminedichloroplatinum(II) and modification of platinum-induced DNA interstrand cross-linking.

1-beta-D-Arabinofuranosylcytosine (ara-C) and hydroxyurea (HU) were investigated as possible inhibitors for the repair of cis-diamminedichloroplatinum(II) (DDP)-induced DNA damage. HU and ara-C were chosen for their known ability to inhibit DNA excision repair following UV irradiation. Work by several groups has suggested that the repair of DDP-induced DNA damage may involve an excision-repair mechanism. The cytotoxic effects of dose, exposure duration, and sequence for the three drugs was studied in a human colon cancer cell line (HT-29) by colony formation assays. Significant synergistic cytotoxicity was seen whether HU + ara-C were given prior to, or following DDP exposure. Cytotoxic synergy was also seen between HU + ara-C themselves. The effect of the combined antimetabolites on the level and persistence of DDP-induced DNA interstrand cross-links was assessed by DNA alkaline elution. These were measured as an indicator of DDP-DNA adduct formation and removal. When HU + ara-C exposure preceded or followed DDP treatment, higher levels of interstrand cross-linking were found at late time points than were seen with DDP alone, suggesting repair inhibition. We conclude that the combination of HU, ara-C, and DDP shows synergistic cytotoxicity, and that this effect may be due in part to inhibition of DDP-induced DNA adduct repair. The concentrations of drugs used in vitro are achievable in humans. On the basis of these results, a Phase I/II clinical trial of the three agents in combination has been initiated.

Cell Survival↗

PubMedDate not supplied

Effects of hydroxyurea in vivo treatment on the antibody response in mice.

In the present work, we investigate the effects of hydroxyurea (HU) treatment given before antigen priming on the antibody response in the mouse. We have studied the response to both thymus-independent and thymus-dependent antigens. With both types of antigens, we have found a two- to ten-fold increase in the number of antigen-specific IgM PFC in the spleens of HU-treated primed mice. In the case of the T-dependent antigens, a simultaneous decrease in the IgG PFC response was also observed in HU-treated mice. These results suggest that major changes in the dynamic equilibrium of the cells of the immune system, induced by HU treatment, may result in different homeostatic regulation, as revealed by the modified pattern of response to exogenous antigens.

Animals↗

PubMed1987

Inhibition of thymidylate synthase in intact L1210 cells by ara-C, daunomycin, hydroxyurea and 3,4-dihydroxybenzylamine.

The use of an in situ assay for thymidylate synthase has shown that a variety of clinically important drugs, including arabinofuranosylcytosine, hydroxyurea, and daunomycin, inhibit thymidylate synthase in intact cells. In contrast to the inhibition observed with 5-fluorodeoxyuridine, inhibition occurs by an indirect mechanism, is delayed in onset, and is incomplete. Inhibition occurred at concentrations that corresponded to those that inhibit DNA synthesis, suggesting that this phenomenon might contribute to the biological action of these agents. Since the inhibition of thymidylate synthase by this indirect mechanism appears to be a general property of drugs that inhibit DNA synthesis, our findings may have important implications for the mechanism of killing of tumor cells, as well as the rationale for combination regimens.

Animals↗