Capecitabine is a novel fluoropyrimidine carbamate, orally administered and rationally designed to undergo tumor-selective activation. Some studies have been proven it to be safe for outpatient treatment and to have significant antitumor activity in colorectal and breast cancer patients. Randomized trials of patients with advanced colorectal cancer using capecitabine versus Leucovorin (LV).5-FU were studied in two groups. Capecitabine results in both a higher response rate and a more favorable toxicity profile than LV.5-FU. In women aged 55 years or more with breast cancer, capecitabine showed at least comparable efficacy to CMF combination therapy. Capecitabine offers a new effective oral treatment option as a single agent for patients with advanced colorectal or breast cancer.

Irinotecan (CPT-11) is a derivative of the chemotherapeutic agent Camptothecin. CPT-11 inhibits the nuclear enzyme topoisomerase I. It has demonstrated a broad spectrum of antitumor activity in preclinical tumor model systems. Significant advances have been made toward the understanding of the pharmacokinetics and schedule dependency of this agent. The principal dose limiting toxicities are diarrhea and leukopenia. CPT-11 has been evaluated using a variety of dosing schedules. Two main schedules have been studied and produce similar activity and side-effects: the "Japanese-North American" one where CPT-11 is given at a weekly dose of 100-150 mg/m2 for 4 consecutive weeks followed by a 2 week rest period, and the "European" one-350 mg/m2 every 21 days. CPT-11 has demonstrated significant clinical activity in the treatment of patients with gastrointestinal, pulmonary, gynecologic, and lymphoid malignancies. A recent randomized trial demonstrated a survival advantage in metastatic non-small cell lung cancer and previously untreated metastatic colorectal cancer. Further study of this agent to determine its role in combination chemotherapeutic regimens is currently underway.

Angiogenesis is known to be a critical process for the tumor growth and metastasis. There are many indigenous role-players in tumor angiogenesis and anti-angiogenesis, where tumor-host interaction may work. A lot of agents with anti-angiogenic activity have been developed for anti-cancer treatment. Several agents including Marimastat, Primostat, Neovastat, Bay-12-9566m, Interferon-alpha, SU101, retinoids, and IM862, are/were under phase-three study. There are still many future-promising results of basic or clinical studies on inhibitors of MMPs, and inhibitors of VEGF/R, Endostatin, somatostatin analogues, COX-2 inhibitors, and others. Most of the combination treatments of antiangiogenetic agent and conventional anticancer agents therapy, or radiation therapy as we reported, showed relatively small or minute increase in toxicity of these cytotoxic treatments.

When a phase I clinical trial is conducted, the dose escalation strategy is most critical. According to the results of preclinical trials, a rapid and safe dose escalation is necessary. In this regard, a pharmacokinetically guided dose-escalation (PGDE) strategy has been developed. An accelerated dose escalation is conducted by PGDE until reaching 40% target AUC. To determine the MTD of target anti-cancer agents, PGDE appears to be useful.

As an induction therapy for advanced lung cancer, a patient received bronchial arterial infusion of 30 mg/m2 of docetaxel (TXT). Two weeks after infusion, although the tumor size was not reduced, the central necrotic area was significantly increased. There were no adverse effects. Nineteen days after infusion, we performed a right lower lobectomy and lymph nodal dissection. The resected specimen was examined by immunohistochemistry and biochemistry. The anti-tumor effects were evaluated clinically and the correlation between arterial TXT infusion therapy and apoptosis was studied. Hematoxylin and eosin staining demonstrated moderately differentiated squamous cell carcinoma associated with central necrosis, and cells with chromatin condensation scattered in both the necrotic areas and the margin of this area. It is thought that these findings were the result of this therapy, rather than just the self-necrosis seen in an untreated group.

We investigated the antiemetic effect, safety and usefulness of granisetron hydrochloride tablets on nausea and vomiting induced by oral anticancer drugs used in chemotherapy for gastric cancer and colorectal cancer. In the present trial, oral administration of granisetron hydrochloride was performed during 5 days after nausea or vomiting. 1) Clinically, the effective rate of granisetron hydrochloride (the percentage of cases in which the drug was assessed as "Remarkably effective" or "Effective") was more than 75% on each day of administration. There were no adverse events or abnormal laboratory tests. 2) In terms of usefulness, granisetron hydrochloride was rated "Extremely useful" or "Useful" in 17 out of 23 cases (78.2%). The above results have shown that granisetron hydrochloride tablets, administrated orally once daily at a dose of 2 mg, have an excellent antiemetic effect, and that this is a safe and useful drug.

It is easy to come into contact with cytotoxic drugs, by touching or inhaling small quantities of the drug-containing aerosols or dusts. Contact with cytotoxic drugs can cause immediate problems, such as dermatitis, dizziness, nausea, and headache. Studies suggest that repeated exposure to small amounts of the drugs many cause organ or chromosome damage, impaired fertility, and even cancer. The evidence is not conclusive, but an approach that will minimize the possible risks is needed.

The incidence of flutamide-induced liver toxicity was studied in 30 consecutive patients with prostate cancer who were treated with total androgen blockage (TAB) therapy (luteinizing hormone releasing hormone [LHRH] analogue and flutamide) in our hospital during the last 3 years and in 20 consecutive patients with prostate cancer who were treated by partial androgen blockage (PAB) therapy (LHRH analogue alone).

Luteinizing hormone-releasing hormone (LHRH) agonists are popularly used drugs in the treatment of prostatic cancer. However, it has been reported that continuation of a low testosterone level following a longterm administration of these drugs reduces the bone mineral density and makes for osteoporosis, which is accountable for fracture, we measured the bone mineral density and bone metabolic markers in the cases who suffered fracture receiving LHRH agonists for prostatic cancer.

Alteration of the p53 gene product occurs frequently during the progression of colorectal cancer. Recently, mutated p53 protein was found to induce the production of anti-p53 antibodies in the serum of patients. The purpose of this study was to evaluate the relationship between p53 status in serum and chemosensitivity in resectable colorectal cancer patients. A total of 35 patients with primary colorectal cancer who underwent surgical treatment were examined by chemosensitivity test with the viable tumor samples using Histoculture Drug Response Assay (HDRA). Serum samples of these patients to test for p53 antibodies were obtained before tumor resection, and assayed in duplicate by using an enzyme-linked immunosorbent assay (ELISA) kit. The inhibition index of 5-FU and CDDP, determined by the HDRA method, in the sero-positive group was significantly lower than that of the sero-negative group (p < 0.01). Furthermore, significant statistical differences in chemosensitivity to 5-FU and CDDP were revealed depending on the presence of serum p53 antibodies. There was no relationship between chemosensitivity assay and tumor marker positivity or clinicopathological features in these patients. Detection of serum p53 antibodies, which reflects p53 mutations in tumor tissue, is a simple method which correlates with chemosensitivity, and may contribute to the selection of favorable chemotherapeutic strategies of colorectal cancer.

Myocardial damage may be induced by several categories of drugs. Adriamycin is one of the most effective chemotherapeutic agents. Unfortunately, it develops a distinctive and life-threatening congestive heart failure by well-characterized, dose-dependent cardiac toxicity. Left ventricular ejection fraction determined using echocardiography or radionuclide angiography does not decrease sensitively and linearly with the adriamycin dose level. Cardiac function is preserved until a critical degree of myocardial damage is reached, after which myocardial performance deteriorates rapidly. Biochemical monitoring may be a novel sensitive and specific method for detecting subclinical myocardial damage. Abnormal cardiac adrenergic neuron activity evaluated with radiolabeled MIBG, impaired myocardial glucose utilization measured with F-18-FDG and plasma brain natriuretic peptide levels increased due to cardiac dysfunction may be particularly sensitive markers of adriamycin cardiotoxicity. It is hoped that prospective clinical study reveals the values of these biochemical markers.

A 40-year-old man was admitted with fever and purpura. He was diagnosed as having acute promyelocytic leukemia, and treated with all-trans retinoic acid. After achieving complete remission, he received consolidation therapy. During the chemotherapy, quadriplegia occurred three times. This was diagnosed as hypokalemic periodic paralysis because of the patient's low serum potassium level. Results of hormone and urine examinations showed no indication of secondary hypokalemia. However, the patient had a history of quadriplegia of unknown etiology at the age of 36. We speculated that in addition to the patient's predisposition to hypokalemic periodic paralysis, chemotherapy including prednisolone, and excessive ingestion of carbohydrate had induced his quadriplegia.

The purpose of this study was to evaluate whether the characteristic change in breast cancer related to chemotherapeutic response (CR) and the effect of invasion and toxicity in the skin and pectoralis muscle exist on MR imaging after intra-arterial infusion chemotherapy. A total of 11 patients with histologically proven breast cancer underwent MR study before and after chemotherapy. Changes in images and the dynamic curve-after-chemotherapy were evaluated, including time to maximum signal intensity (SI) and the early phase enhance ratio (EPER) in the tumor. In the tumor, changes in the dynamic curve, time to maximum SI, EPER and necrosis did not correlate with CR, but change in SI on T2-weighted images was suggested to do so. Changes in the dynamic curve and images in the pectoralis muscle and in images on the skin were suggested to correlate with CR. In addition, images changed for the worse in many cases of invasion and toxicity in the pectoralis muscle and in some cases of invasion in the skin. In conclusion, tumors had fewer imaging changes correlating with CR after intra-arterial infusion chemotherapy. Changes for the worse in images of the pectoralis muscle and skin may be useful for the evaluation of invasion.

It has been shown that arsenic trioxide (As2O3) may induce hematologic remissions in patients with acute promyelocytic leukemia (APL) refractory to all-trans retinoic acid (ATRA). We reported on a patient with ATRA and drug-resistant APL that was successfully treated with As2O3. The patient had been given a diagnosis of typical APL and was treated with ATRA and chemotherapy for 12 months. He achieved complete remission (CR), but leukemia relapsed with 43% APL cells in the bone marrow in the 16th month of treatment. ATRA and cytarabine plus daunorubicin were administered; however, the APL cells in the bone marrow increased to 97.2%. As2O3 was initiated intravenously, and bone marrow showed a decrease of APL cells (6.7%) and a partial differentiation after 9 days. The patient received idarubicin (IDA) and steroid pulse because of the development of ATRA-like syndrome, and achieved CR 37 days after the initiation of As2O3. He received an additional 2 courses of As2O3 with IDA, and is in CR. These results demonstrated the therapeutic efficacy of As2O3 in treating ATRA and drug-resistant APL.

We examined the chemosensitivity of non-small cell lung cancer (NSCLC) tissues to CDDP, 5-FU, ADM, MMC, ETP and SN38 using histoculture drug response assay (HDRA). One-hundred and thirty surgical specimens from NSCLC patients who were not given preoperative chemotherapy were used. The inhibition indexes of CDDP, 5-FU, MMC, ADM, ETP and SN38 were 39.1 +/- 18.2%, 48.0 +/- 19.7%, 63.3 +/- 17.7%, 47.6 +/- 22.0%, 36.9 +/- 21.1%, and 37.9 +/- 25.2%, respectively. Inhibition indexes were above the cutoff level, i.e., 'judged sensitive,' in 40 cases (31.3%) for CDDP, 34 cases (27.4%) for 5-FU, 54 cases (44.3%) for MMC, 36 cases (33.0%) for ADM, 29 cases (29.8%) for ETP, and 34 cases (37.4%) for SN38, respectively. In almost one-third of patients, the inhibition indexes of all drugs were under cutoff levels. Correlations between in vitro chemosensitivity data and patient responses to chemotherapy were obtained from 16 evaluable patients, and a 44.4% true positive rate and a 100% true negative rate were observed. Our results with HDRA for NSCLC showed a high incidence of intrinsic multidrug resistance. HDRA may help doctors to avoid non-effective chemotherapy for NSCLC patients.

We report a case of transitional cell carcinoma in the left renal pelvis, which occurred in a 24-year-old man. He had been treated with cyclophosphamide (CPM) for a period of 27 months for retroperitoneal rhabdomyosarcoma diagnosed at the age of 10. At first 1.2 g CPM had been given twice intravenously for 3 months, followed by oral administration of 41 g CPM for 23 months. Drip infusion pyelography revealed a filling defect in the left renal pelvis. A left renal pelvic tumor was strongly suspected on computerized tomography and magnetic resonance imaging. Left nephroureterectomy was then performed. Histological diagnosis of the left renal pelvic tumor was transitional cell carcinoma, grade 2, pT1N0M0. No recurrence was defected 17 months later. This case seems to be the second case of cyclophosphamide-induced upper urothelial carcinoma reported in Japan.

Docetaxel (TXT) has been shown to be an up-regulator of human pyrimidine nucleoside phosphorylase (PyNPase) in tumors. We have tried to use the combination of low-dose weekly TXT with 5'-DFUR (LD + D) in patients with advanced or metastatic breast cancer. In this study, we compared the clinical efficacy of LD + D with that of conventional full-dose TXT (FD) and that of low-dose weekly TXT (LD). Twenty-one patients received 3 or 4 cycles of FD 60 mg/m2 every 3 or 4 weeks (group I), 14 patients received 8 cycles of LD 20-30 mg/m2 every week (group II) and 25 patients received 8 cycles of LD 20-30 mg/m2 weekly with oral 5'-DFUR 600-1,200 mg per day (group III). The overall response rates of groups I, II and III were 29%, 29% and 52% (p = 0.24), respectively. Grade 3-4 neutropenia was observed in 91% of group I, 6% of group II and 3% of group III. Nausea was present in 27% of group I, 28% of group II and 40% of group III. Higher incidence of gastrointestinal symptoms was found in LD + D, but the symptoms abated when the doses of 5'-DFUR were reduced. Low-dose weekly TXT with oral 5'-DFUR produced a higher response rate, but less hematologic toxicity than full-dose TXT, suggesting that this combination therapy is clinically useful and may be effective for patients with advanced or metastatic breast cancer.

A nationwide questionnaire survey was carried out on low-dose cisplatin-5-FU therapy for solid malignant tumors (mostly stomach and colon cancer) regarding its antitumor as well as adverse effects. The regimen was defined as 4 weeks administration of cisplatin 2-5 mg/body, 5 days a week, which was used in 47% of 82 institutions studied. Cases were classified into an Ab regimen (86 cases) with cisplatin 3-5 mg/body, and a Bb regimen (122 cases) with cisplatin 6-30 mg (mostly 10 mg)/body, both of which were given 5-FU 300-500 mg/body daily. The antitumor effect (CR + PR) was shown to be slightly higher in the Bb regimen than in the Ab regimen, and was 35% overall. Very few adverse effects appeared with either regimen for mostly major digestive, hepatic and renal functions, except for myelodepressions (leucopenia and thrombocytopenia), which were more than grade 3 in only a few percent with the Ab regimen, and a little more than 10% with the Bb regimen. The advantages and disadvantages of the A/Bb regimens appeared to be counter-balanced in terms of their antitumor and adverse effects. Most institutions using the Ab regimen favored repeating the regimen cycle as much as possible. Those using more than 6 cycles accounted for about 20% of hospitals.