Cancer hydroxyurea

Hussey DH, Abrams JP. Combined therapy in advanced head and neck cancer hydroxyurea and radiotherapy. Prog Clin Cancer 1975 6 79-86. 

Inhibition of ribonucleoside diphosphate reductase by hydroxyurea. Cancer Res 1968 28 1559-1565. 

Colvin M, Bono VH Jr The enzymatic reduction of hydroxyurea to urea by mouse liver. Cancer Res. 1970 30 1516-1519. 

Ask A, Persson L, Rehnholm A, Frostesjo L, Holm I, Heby O (1993) Development of resistance to hydroxyurea during treatment of human myelogenous leukemia K562 cells with alpha-difluoromethylornithine as a result of coamplification of genes for ornithine decarboxylase and ribonucleotide reductase R2 subunit. Cancer Res 53 5262-5268... 

Yen Y, Grill SP, Dutschman GE, Chang C-N, Zhou BS, Cheng Y-C (1994) Characterization of a hydroxyurea-resistant human KB cell line with supersensitivity to 6-thioguanine. Cancer Res 54 3686-3691... 

Kies ME, Haraf D, Rosen F, Stenson K, List M, Brockstein B, Chung T, Mittal B, Pelzer H, Portugal L, Rademaker A, Weichselbaum R, Vokes EE. Concomitant Infusional Paclitaxel and Fluorouracil, Oral Hydroxyurea, and Hyperfractionated Radiation for Locally Advanced Squamous Head and Neck Cancer. J Clin Oncol 2001 19 1961-1969. 

Hydroxyurea is an oral agent that inhibits ribonucleotide diphosphate reductase and interferes with the synthesis of DNA, specifically the S phase of the cell cycle. Sinclair et al. have demonstrated in preclinical animal models that hydroxyurea may inhibit cells from leaving the Gj radiosensitive phase and entering the radioresistant S phase (9). Early studies have demonstrated little or no efficacy associated with the use of single-agent hydroxyurea (10). It has received FDA approval in the use of head and neck cancer when administered concomitantly with radiotherapy based upon promising results from earlier studies (11). 

Sinclair WK. Hydroxyurea effects on Chinese hamster cells grown in culture. Cancer Res 1967 27 297-308. 

Vokes EE, Haraf DJ, Panje WR, et al. Hydroxyurea with concomitant radiotherapy for locally advanced head and neck cancer. Semin Oncol 1992 19 53-58. 

Haraf DJ, Kies M, Rademaker AW, et al. Radiation therapy with concomitant hydroxyurea and fluorou-racil in stage II and III head and neck cancer. J Clin Oncol 1999 17 638-644. 

BrocksteinB, Haraf DJ, Stenson K, etal. Phase I study of concomitant chemoradio therapy with paclitaxel, fluorouracil, and hydroxyurea with granulocyte colony-stimulating factor support for patients with poor-prognosis cancer of the head and neck. J Clin Oncol 1998 16 735-744. 

Kies MS, Haraf DJ, Rosen F, etal. Concomitant infusional paclitaxel and fluorouracil, oral hydroxyurea, and hyperfractionated radiation for locally advanced squamous head and neck cancer. J Clin Oncol 2001 19 1961-1969. 

Humerickhouse RA, Haraf D, Stenson K, et al. Phase I study of irinotecan (CPT-11), 5-FU, and hydroxyurea with radiation in recurrent or advanced head and neck cancer. Proc Anna Meet Am Soc Clin Oncol 2000 19 A1650. 

Spencer SA, Harris J, Wheeler RH, et al. RTOG 9610 Reirradiation with concurrent hydroxyurea and 5-fluorouracil in patients with squamous cell cancer of the head and neck, hit J Radiat Oncol Biol Phys 2000 51 1299-1304. 

Until recently, hydroxyurea was prominent in most of the prospective randomized trials of chemoradiation for cervical cancer. One must understand the early trials of chemoradiation with hydroxyurea to understand the design of later chemoradiation trials. 

Although flaws in these studies of hydroxyurea left their results open to question, the GOG was convinced that the weight of the evidence supported inclusion of hydroxyurea in the control arms of future trials. In the early 1980s, 308 patients with stages IIB-IVA cervical cancer were randomly assigned to receive radiation therapy with concurrent hydroxyurea or radiation therapy with concurrent misonidazole. A preliminary review... 

North American prospective trials of radiation sensitizers for cervical cancer have focused on the use of cisplatin, fluorouracil, and hydroxyurea. However, a number of other drugs also hold promise as effective radiation sensitizers for cervical cancer, including mitomycin C, epirubicin, paclitaxel, and carboplatin. 

Sinclair W. The combined effect of hydroxyurea and x-rays on Chinese hamster cells in vitro. Cancer Res 1968 28 198-201. 

Hreshchyshyn MM. Hydroxyurea with irradiation for cervical carcinoma—preliminary report. Cancer ChemRep 1968 52 601-602. 

Piver M, Barlow J, Vongtama V, et al. Hydroxyurea and radiation therapy in advanced cervical cancer. Am J Obstet Gynecol 1974 120 969-972. 

Piver M, Vongtama V, Emtrich L. Hydroxyurea plus pelvic radiation versus placebo plus pelvic radiation in surgically staged stage IIIB cervical cancer. J Surg Oncol 1987 35 129-134. 

Hreshchyshyn MM, Aron BS, Boronow RC, et al. Hydroxyurea or placebo combined with radiation to treat stages IIIB and IV cervical cancer confined to the pelvis. Int JRadiat Oncol Biol Phys 1979 5 317-322. 

The management of cancer includes treatment with alkylating agents (nitrogen mustards and alkyl sulfonates), antimetabolites (methotrexate and purine analogs), natural products (vinca alkaloids and antibiotics), miscellaneous compounds (hydroxyurea, procarbazine, and cis-platinum), hormones (estrogens and corticosteroids), and radioactive isotopes (see Chapter 62). 

Reardon DA et al (2009) Phase I pharmacokinetic study of the vascular endothelial growth factor receptor tyrosine kinase inhibitor vatalanib (PTK787) plus imatinib and hydroxyurea for malignant glioma. Cancer 115 2188-2198... 

Drugs used in cancer chemotherapy are cytotoxic drugs, hormones, plant derivatives, radioactive isotopes, and miscellaneous agents (e.g., procarbazine, hydroxyurea, mitotane). The plant-based drugs vincristine, vinblastine, vinorel-bine, etoposide, and campothecins. Radioactive isotopes, such as 131 iodine (131 I), are used in the treatment of thyroid tumors. Cytotoxic drugs (e.g., cis-platin, cyclophosphamide, 6-mercaptopurine, 5-fluorouracil, and methotrexate are used for the treatment of cancer. 

Marked increments in response were observed with the incorporation of cisplatin into combination regimens response rates greater that 50% were reported in Phase-Ill studies of cisplatin/ifosfamide, cisplatin/ifosfamide/ bleomycin, and cisplatin/5-FU [188-190]. Randomized trials of these combinations administered prior to radiotherapy in locally advanced disease have not shown a survival advantage however, a recent GOG trial of concurrent cisplatin or cisplatin/5-FU/hydroxyurea and radiation was associated with significantly improved progression-free survival versus concurrent hydroxyurea and radiation in patients with Stage IIB-IVA cervical cancers [191]. Combined cisplatin and paclitaxel produced responses in 9 of 11 patients in a recent GOG study [192] and will be the focus of larger trials in the future. 

A large number of compounds in category 3 act at different sites in the pathways for purine and pyrimidine biosynthesis. These compounds are very toxic for rapidly growing tumors and bacteria, making them useful in cancer chemotherapy and treatment of bacterial infections. 6-Mercaptopurine is a potent inhibitor of purine biosynthesis, and 5-fluorouracil inhibits thymidylate synthesis. Some compounds, such as hydroxyurea and sulfonamides, inhibit the synthesis of both purine and pyrimidine nucleotides. These are only a few of the many compounds useful in treating cancer and infectious diseases (see Chapter 10). 

It possessed cytotoxicity for six cell lines (IC50 l 100pg/mL) and antitumor effects on human nasopharyngeal cancer (CNE2, SUNE-1) and human liver cancer (BEL-7402) in nude mice. Recently artesunate has been analyzed for its antitumor activity against 55 cell lines.It was most active against leukemia and colon cancer cell lines. It is notable that no CEM leukemia sublines, which are resistant to either doxorubicin, vincristine, methotrexate, or hydroxyurea, showed cross resistance to artesunate. 

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