Irinotecan hydrochloride and topotecan hydrochloride, analogues of camptothecin, are a new class of chemotherapeutic agents possessing a novel mechanism of action, targeting type I DNA toposiomerase. Irinotecan hydrochloride has significant in vitro activity against a variety of solid tumors, including those particularly resistant to other cytotoxic agents, and therefor, may allow the development of novel combinations of chemotherapeutic regimens. Also, a synergistic effect of irinotecan hydrochloride with cisplatin has been observed in preclinical studies. On the basis of phase I studies of irinotecan hydrochloride using various schedules, 100mg/m² given as a 90-min iv infusion once per week appears to be an appropriate dosage schedule for subsequent clinical trials in patients with solid tumors. In chemotherapy-naive patients with advanced non-small cell lung cancer, a response rate of 32% to irinotecan hydrochloride monotherapy has been demonstrated, although this has been improved to within a range of 48%-54% using irinotecan hydrochloride in combination with cisplatin. Irinotecan hydrochloride as a single egent is also active against small cell lung cancer that has relapsed or proved refractrory to first-line chemotherapy, with a response rate 47%. Irinotecan hydrochloride is more active when combined with cisplatin as a first-line chemotherapy for extensive small cell lung cancer, giving a response rate of 86%. Phase III studies of combination chemotherapy with irinotecan hydrochloride and cisplatin for advanced non-small cell lung cancer and for extensive small cell lung cancer are currently being conducted in Japan. Topoisomerase I and topoisomerase II targeting chemotherapy is considered to have interesting therapeutic potential. The combination of irinotecan hydrochloride and etoposide was investigated with simultaneous or sequential administration of the two drugs daily for three consecutive days every 4 weeks. However, the response rate for this regimen using this schedule with prophylactic administration of granulocyte colony-stimulating factor (G-CSF) was no better than that of cisplatin-based combination chemotherapy for advanced non-small cell lung cancer. Preclinical studies have suggested that the antitumor activity of irinotecan hydrochloride is time-and dose-dependent. French investigators have recommended a single dose of 500mg/m²-double the dose used in Japan-with the support of high-dose loperamide for control of diarrhea and without G-CSF and GM-CSF, and have suggested a dose-dependent antitumor effect in colorectal cancer. Additional evaluation and comparison of the dose and schedule of topoisomerase I inhibitors producing maximal therapeutic synergy in combination with other anticancer agents are needed in order to develop efective chemotherapies for lung cancer.

View full abstract

Irinotecan (CPT-11) is a semi-synthetic derivative of camptothecin (CPT). CPT-11 is metabolized to SN-38 and exerts anticancer activity through its inhibitory action on type-I DNA topoisomerase. SN-38 (CPT-11) has demonstrated potent inhibition of growth of various types of cancer cells. In phase I II studies, objective response rated ranged from 21 to 32% for cob-rectal cancer and from 20 to 25% for gastric cancer, and the most frequent adverse events were neutropenia and diarrhea. Those hopeful results have stimulated both clinical and preclinical research to increase its therapeutic efficacy by combination with other anticancer agents. The phase I 11 study of CPT-11 with CDDP in Japan has revealed a high response rate of 42% for gastric cancer. A CPT-11/5-fluorouracil (5-FU) combination was investigated in phase I-11 studies in patients with advanced cob-rectal cancer: Response rates ranged from 14% to 67%. In the laboratory, efforts have been directed towards understanding the critical determinants of irinotecan-induced cytotoxicity, seeking the best modalities to improve CPT-11 effectiveness. We have shown that the plasma-transmembrane potential may play an important role in CPT-11 resistance. Since doxorubicin (ADR), like CPT-11 (SN-38), is positively charged in a physiological condition, a synergistic effect in co-treatment with ADR is not hopeful. On the other hand, CPT-11 treatment induces an increase in topo-II mRNA expression after 24 to 48 h. CPT-11 can modulate topo-II levels to enhance the effect of topo-11 inhibitors such as ADR. Sequential treatment with CPT-11 and ADR is more active than with CPT-11/MMC and CPT-11/CDDP. Thus we suggest that CPT-11/ADR is the best combination for gastrointestinal cancers.

View full abstract

Concerning anticancer drugs of new category: called topoisomerase I inhibitors, i. e., irinotecan hydrochloride (CPT-11) and topotecan hydrochloride (TPT), we report the pharmaceutical properties and the results of clinical studies that were focused on cancers of the ovary and uterine cervix, and describe the background and current status of development of these drugs. CPT-11 is a semisynthetic derivative of camptothecin, that is an antitumor alkaloid contained in Camptotheca acuminata (Kiju) of Chinese origin. Since a metabolite of CPT-11, SN-38, exhibits a strong effect in inhibiting cellular growth, CPT-11 is believed to be a pro-drug. TPT, on the other hand, is a derivative of water-soluble camptothecin, and unlike CPT-11, the unchanged TPT is considered to be active. The mechanism of action of both CPT-11 and TPT is suggested to be selective ihnhibition of the action of type-I DNA topoisomerase, and inhibition of cancer cell growth, leading to antitumor actions. Both drugs have a wide antitumor spectra, and strong both show antitumor effects against ovary and cervical cancers that have been confirmed in in vitro and in vivo experiments. The dose limiting factors (DLF) of CPT-11 are diarrhea and leukopenia, and that of TPT is leukopenia, especially neutropenia. The optimal dosage regimens of CPT-11 for ovary and cervical cancers are suggested as follows: Regimen A: 100mg/m² administered once a week, and Regimen B: 150 mg/m' administered once in two weeks. Various administration methods have been investigated in phase I clinical studies of TPT, and 5-day repeated administration of 1.5mg/m²/day and 1.2mg/m²/day are recommended for overseas and in Japan, respectively. The results of clinical studies on administration of CPT-11 or TPT alone by this regimen, and the appropriateness and effects of combined use with other anticancer drugs are summarized here. Moreover, the recently-reported results of a large-scale randomized clinical comparative study of TPT and paclitaxel (PLT) are described.

View full abstract

Pharmacokinetic parameters of pazufloxacin cefteram pivoxil faropenem cefditoren pivoxil and sparfloxacin were studied in elderly patients with lower respiratory tract infection. The values of T_max and T_1/2 in the elderly were higher for all drugs than in young healthy volunteers, although the values of C_max showed no difference between the two groups. AUC values varied with the drug. We did notfind a relationship between pharmacokinetic parameters and the blood chemistry data in this study, although it is obvious that variation in drug pharmacokinetics depends upon liver and renal function. So it is important to know whether the route of excretion of the drug is via the urine or bile, when the elderly are treated with antimicrobial drugs. Even if blood chemistry data show a normal range, liver and renal functions in the elderly slowly decrease with age in general. In summary the adequate dose of an antimicrobial drug for the elderly should be carefully determind in the treatment of lower respiratory tract infection.

View full abstract