Prevention of chemotherapy-induced alopecia in rats by CDK inhibitors.

Most traditional cytotoxic anticancer agents ablate the rapidly dividing epithelium of the hair follicle and induce alopecia (hair loss). Inhibition of cyclin-dependent kinase 2 (CDK2), a positive regulator of eukaryotic cell cycle progression, may represent a therapeutic strategy for prevention of chemotherapy-induced alopecia (CIA) by arresting the cell cycle and reducing the sensitivity of the epithelium to many cell cycle-active antitumor agents. Potent small-molecule inhibitors of CDK2 were developed using structure-based methods. Topical application of these compounds in a neonatal rat model of CIA reduced hair loss at the site of application in 33 to 50% of the animals. Thus, inhibition of CDK2 represents a potentially useful approach for the prevention of CIA in cancer patients.

Clinical experience with leucovorin and 5-fluorouracil.

Two trials of leucovorin (LV) and 5-fluorouracil (5-FU) in patients with metastatic colorectal cancer were done, both using a 3-day loading dose and then weekly doses to minimize toxicity. The first trial used LV administered by intravenous infusion with a constant dose of 5-FU 400 mg/m2, and the second trail used oral LV with increasing doses of 5-FU. In the first trail, 45 eligible patients (20 with and 25 without previous therapy) were treated. Toxicity usually consisted of diarrhea or weakness and was controlled by delaying or decreasing the 5-FU dose. Subjective responses occurred in 75% of patients but did not correlate with antineoplastic effect. Objective responses were seen in 36% and stabilization of disease in 31% of patients; these correlated with prolonged survival. Median survival was 8 months for patients with previous treatment and 10 for those without. Twelve-month survival was 32% and 40%, respectively. There was no correlation between the development of toxicity and response or survival. The second trial was conducted recently in cooperation with Duke University to determine toxicity and efficacy of oral LV with intravenous 5-FU before a randomized trial of this combination versus placebo with intravenous 5-FU. Eighteen patients were treated, and serum levels of folates were obtained on ten. First toxicity occurred at 5-FU doses ranging from 375 to 850 mg/m2, and consisted of diarrhea in nine, lethargy in seven, nausea/vomiting in four, dermatitis in four, conjunctivitis in two, hypersalivation in two, stomatitis in one, and profound granulocytopenia in one. Response rate was 35%, and stabilization was 35% with median survival of 14 months. Twelve-month survival was 56%.

Clinical experience with CF-FUra.

Two trials of CF-FUra in patients with metastatic colorectal cancer were performed, both using a 3 day loading dose and then weekly maintenance doses to minimize toxicity. The first trial used CF by IV infusion with constant dose of FUra 400 mg/m2, and the second trial used oral CF with escalating doses of FUra. In the first trial, 45 eligible patients (20 with and 25 without prior therapy) were treated. Toxicity usually consisted of diarrhea or weakness and was controlled by delaying or decreasing 5FU dose. Subjective responses occurred in 75% of patients but did not correlate with antineoplastic effect. Objective responses were seen in 36% and stabilization of disease in 31% of patients, and correlated with prolonged survival. Median survival was 8 months for patients with prior treatment and 10 for those without, and 12 month survival was 32% and 40%, respectively. There was no correlation between the development of toxicity and response or survival. The second trial was recently conducted in cooperation with Duke University to determine toxicity and efficacy of oral CP with IV FUra prior to a randomized trial of this combination versus placebo with IV FUra. Eighteen patients were treated and serum levels of folates were obtained on 10. First toxicity occurred at FUra doses ranging from 375 to 850 mg/m2, and consisted of diarrhea in 9, lethargy in 7, nausea/vomiting in 4, dermatitis in 4, conjunctivitis in 2, hypersalivation in 2, stomatitis in 1, and profound granulocytopenia in 1. Response rate was 35% and stabilization was 35% with median survival of 14 months and 12 month survival of 56%.

Antibacterial activity and mechanism of action of 3'-azido-3'-deoxythymidine (BW A509U).

The thymidine analog 3'-azido-3'-deoxythymidine (BW A509U; azidothymidine [AZT]) had potent bactericidal activity against many members of the family Enterobacteriaceae, including strains of Escherichia coli, Salmonella typhimurium, Klebsiella pneumoniae, Shigella flexneri, and Enterobacter aerogenes. AZT also had bactericidal activity against Vibrio cholerae and the fish pathogen Vibrio anguillarum. AZT had no activity against Pseudomonas aeruginosa, gram-positive bacteria, anaerobic bacteria, Mycobacterium tuberculosis, nontuberculosis mycobacteria, or most fungal pathogens. Several lines of evidence indicated that AZT must be activated to the nucleotide level to inhibit cellular metabolism: AZT was a substrate for E. coli thymidine kinase; spontaneously arising AZT-resistant mutants of E. coli ML-30 and S. typhimurium were deficient in thymidine kinase; and intact E. coli ML-30 cells converted [3H]AZT to its mono-, di-, and triphosphate metabolites. Of the phosphorylated metabolites, AZT-5'-triphosphate was the most potent inhibitor of replicative DNA synthesis in toluene-permeabilized E. coli pol A mutant cells. AZT-treated E. coli cultures grown in minimal medium contained highly elongated cells consistent with the inhibition of DNA synthesis. AZT-triphosphate was a specific DNA chain terminator in the in vitro DNA polymerization reaction catalyzed by the Klenow fragment of E. coli DNA polymerase I. Thus, DNA chain termination may explain the lethal properties of this compound against susceptible microorganisms.

In vitro and in vivo efficacy of the combination trimethoprim-sulfamethoxazole against clinical isolates of methicillin-resistant Staphylococcus aureus.

The in vitro susceptibilities of 16 independent, geographically distinct clinical isolates of methicillin-resistant Staphylococcus aureus to trimethoprim (TMP) in combination with sulfamethoxazole (SMX) were evaluated. Although methicillin-resistant S. aureus strains appear to be universally resistant to SMX, the combination TMP-SMX was found to be synergistic in vitro (in combination, the MICs of both drugs decreased 6- to 25-fold) as well as in vivo (5- to 6-fold reduction in TMP at 50% effective doses).