thioguanine-anhydrous and Carcinoma--Non-Small-Cell-Lung

To evaluate a combination of thioguanine, procarbazine, dibromodulcitol, CCNU (CCNU), fluorouracil, and hydroxyurea (TPDC-FuHu), designed to improve the efficacy of CCNU, in the treatment of recurrent metastatic brain tumors.. One hundred fifteen patients with progressive or recurrent metastatic brain tumors that failed to respond to surgery and/or radiation therapy were enrolled onto a multicenter prospective study between 1989 and 1995. Patients received TPDC-FuHu in a repeated cycle every 6 weeks until recurrence or until they completed six courses.. Ninety-seven patients were assessable at the end of the study. Forty-eight had lung cancer (39 non-small-cell [NSCLC] and nine small-cell [SCLC]), 28 had breast cancer, nine had melanoma, and 12 had adenocarcinoma of different origins (three colon, two kidney, one bladder, one stomach, and five of unknown origin). The response and stable disease (SD) rate (overall response rate) was 52%, 66%, 60%, and 22% in patients with NSCLC, SCLC, breast cancer, and melanoma, respectively. Median time to progression (MTP) was 12, 26, 12, and 6 weeks, respectively, for the four groups. Side effects were mild to moderate in the majority of patients. Severe myelosuppression (grade 4) occurred in only 11% of the patients.. TPDC-FuHu chemotherapy is an active treatment against recurrent brain metastases from breast cancer and SCLC, and to a lesser extent from NSCLC. This regimen is well tolerated and has acceptable toxicity.

Topics: Adenocarcinoma; Adult; Age Factors; Aged; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Breast Neoplasms; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Disease Progression; Female; Fluorouracil; Humans; Hydroxyurea; Lomustine; Lung Neoplasms; Male; Middle Aged; Mitolactol; Procarbazine; Prospective Studies; Thioguanine

This randomized phase II study was designed to evaluate the activity of intravenous 6-thioguanine (6-TG) as a single agent and the combination of cisplatin and 5-fluorouracil (5-Fu) modulated by oral leucovorin (PFL) in patients with advanced non-small cell lung cancer (NSCLC). Eligible patients had measurable or evaluable stage III B or IV NSCLC, had no received prior chemotherapy and had a performance status of 0-2. Patients were randomized to treatment with intravenous 6-TG at 55 mg/m2 administered over 30 minutes for 5 consecutive days and repeated every 35 days, or PFL chemotherapy with cisplatin 100 mg/m2 on day 1, 5-FU 800 mg/m2/day as a continuous intravenous infusion over 5 days and oral leucovorin administered at 100 mg every 4 hours during the entire duration of the cisplatin and 5-FU infusions. PFL was repeated every three weeks. Ninety-five eligible patients were randomized, 46 to 6-TG and 49 to PFL. Response rates were 4% for 6-TG (95% confidence interval 0.5%-14.8%, 1 partial, and 1 complete response) and 29% (16.6%-43.3%) for PFL (all partial). The median time to treatment failure was 2 and 4 months, respectively, and the median survival times were 6 and 10 months, respectively. Toxicities with 6-TG were, generally, mild to moderate but severe or life-threatening granulocytopenia was observed in 21% of patients. With PFL, mucositis was dose-limiting, and 78% of patients had severe or life-threatening mucositis. This led to dose reduction of 5-FU and leucovorin during subsequent cycles or treatment termination in 82% of patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cisplatin; Drug Administration Schedule; Female; Fluorouracil; Follow-Up Studies; Humans; Infusions, Intravenous; Leucovorin; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Survival Rate; Thioguanine

Topics: Aged; Carcinoma, Non-Small-Cell Lung; Drug Evaluation; Female; Humans; Infusions, Intravenous; Lung Neoplasms; Male; Middle Aged; Thioguanine

The structure-activity relationship studies of ethyl 2-amino-6-cyclopentyl-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate (1, HA 14-1), an antagonist of the antiapoptotic Bcl-2 proteins, are reported. A series of analogues of 1 with varied functional groups at the 6-position of the chromene ring were synthesized. These candidates were evaluated for their binding interactions with three antiapoptotic proteins: Bcl-2, Bcl-XL, and Bcl-w. They were also assayed for their in vitro cytotoxicities against a set of Jurkat cells with varied levels of Bcl-2 and Bcl-XL proteins and a non-small-cell lung carcinoma cell line (NCI-H460). It was found that the 6-bromo of 1 was not essential for its bioactivity and the 6-position can accommodate a variety of alkyl groups. 1 and its analogues bind to all of the three antiapoptotic Bcl-2 proteins tested. Positive correlations were observed between the binding affinities of these candidates to the antiapoptotic Bcl-2 proteins and their in vitro cytotoxicities, suggesting that the antiapoptotic Bcl-2 proteins are likely to be the cellular targets of 1 and its analogues. (In this study, the binding interactions of the small molecules to antiapoptotic Bcl-2 proteins were studied by assaying their abilities to compete against a Bak peptide binding to the antiapoptotic Bcl-2 proteins. Inhibitory constants, instead of dissociation constants, were obtained in such assays. The term "binding affinity" is used in this article for simplicity.) The most active compound, 3g, had a >3-fold increase of binding affinity to the antiapoptotic Bcl-2 proteins and a >13-fold increase of in vitro cytotoxicity over 1. Though Jurkat cells with transgenic overexpression of Bcl-2 or Bcl-XL protein can develop resistance to standard cancer therapies, such cells failed to develop resistance to 1 based candidates. 1 also sensitizes Jurkat cells to cisplatin. These studies provide further support that 1 and its analogues function as antagonists for antiapoptotic Bcl-2 proteins and that they have the potential, either as a single agent or as a combination therapy with other anticancer agents, to treat cancers with the overexpression of antiapoptotic Bcl-2 proteins.

Topics: Antineoplastic Agents; Apoptosis; Apoptosis Regulatory Proteins; bcl-X Protein; Benzopyrans; Carcinoma, Non-Small-Cell Lung; Cisplatin; Drug Resistance, Neoplasm; Enzyme Inhibitors; Humans; Jurkat Cells; Lung Neoplasms; Nitriles; Proto-Oncogene Proteins c-bcl-2; Structure-Activity Relationship; Tumor Cells, Cultured