Informed consent in phase I trials involves very difficult problems related to experimental factors of the phase I trial, a toxicity study conducted in human cancer patients. However, this is the first clinical step in new drug development, and patients must participate in phase I only when there is full disclosure of correct trial information. Disclosure should include the purpose of the trial, the procedure, and the risk/benefits related to the trial. Informing the patient of the cancer diagnosis and the extent of disease is also necessary before entry into a phase I trial. Although phase I trials are conducted with the precious contribution of patients, it is important that informed consent should not become a type of legal contract. Informed consent in phase I trials is an essential process, just like a roundtable discussion of patient and physician before fighting an incurable cancer.

In this report, we present some current problems in the development of new anticancer agents for new molecular targets in the development process: basic research, developing research and clinical trials. Also new proposals are made to solve these problems from our corporate point of view. It will be necessary to work out new rational methods to evaluate toxicity and efficacy considering the mechanisms and pharmacokinetics of drugs to develop new anticancer agents. Changes in clinical evaluation criteria for antitumor agents, from tumor size to survival time an improvement of QOL, will mean increased costs and a longer time for clinical trials. Given these conditions, it will be necessary for companies to co-operate with public research institutes in order to develop new anticancer agents, and to revise the guidelines and systems of clinical trials.

The design, antitumor activity in vitro as well as in vivo, and mechanism of CNDAC have been described. CNDAC had potent antitumor effects against various solid tumors in vitro as well as in vivo. CNDAC was phosphorylated by deoxycytidine kinase, followed by certain nucleotide kinases to afford its 5'-triphosphate (CNDACTP), which was a potent inhibitor of DNA polymerase alpha. Using a chain-extension method with Vent (exo-) DNA polymerase and a short primer/template system, we found that CNDACTP was incorporated into the primer. After further chain-extension reaction of the primer containing CNDAC at the 3'-terminus, chain elongation was not observed. Therefore, CNDACTP appeared to act as a chain-terminator. Analyses of the structure of the 3'terminus in the primer revealed the presence of ddCNC together with CNDAC and CNDC. The existence of ddCNC in the 3'-end of the primer would be due to the self-strand-break by the nucleotide incorporated next to CNDAC.

A new human endometrial adenocarcinoma cell line, Watanabe cells, was established from the ascitic fluid of a relapsed endometrial adenocarcinoma obtained from a 58-year-old woman; this cell line has been maintained in vitro for more than 3 years and 8 months. The cells formed a monolayer in a mosaic fashion and tended to pile up and formed a hemicyst. The population boubling time was 60.0 hours at the 10th generation. The modal chromosomal number of the cells was in the diploid range. The histology of tumors induced by this cell line in athymic nude mice showed poorly differentiated adenocarcinoma, while the initial tumor was a well differentiated adenocarcinoma. Estrogen and progesterone receptors (ER, PR) were demonstrated in the original tumor, whereas ER but not PR were present in the tumors induced in nude mice. CA125, CA19-9 and other tumor markers were positive in culture media of this cell line. The cells showed intrinsic cisplatin-resistance (50% inhibition concentration: > 10 micrograms/ml) at 120 hours of exposure by MTT assay. We believe this cell line will be useful for investigating the mechanisms of progesterone therapy, the biological behaviors of the tumor markers and mechanisms of chemotherapeutic resistance in endometrial carcinoma.

The endpoint of chemosensitivity test lies to extend the survivals of cancer patients using the adapted antitumor agents determined by the assay. Although the overall predictive accuracy of chemosensitivity test was 79% (117/149) for gastrointestinal carcinomas, no remarkable survival benedit was obtained even in the "true positive" cases. Two retrospective and one semi-prospective studies were conducted using MTT assay or histoculture drug response assay, indicating that these tests will be useful in evaluating the adoptive adjuvant cancer chemotherapy for advanced gastric cancer by increasing the patients' survivals. The chemosensitivity test should be changed its position from laboratory to clinic through an acceptance of the assay as social medical insurance.

The chemosensitivity test should be performed to individualize the chemotherapy for patients with gastrointestinal cancer, which is one of the tumors most refractory to treatment by anticancer drugs. The present study was designed to determine the chemosensitivity in fresh human gastrointestinal cancer, using highly purified tumor cells, and the correlation of this sensitivity with clinical response. The clinical responses were obtained in 15 of the 25 patients, and 5 of the 15 patients with gastric cancer and colorectal cancer, respectively. The inhibition rates for anticancer drugs in responders were higher than in nonresponders. Thus, it is suggested that the chemotherapy according to the results of the MTT assay is effective in patients with gastrointestinal cancer.

The in vitro chemosensitivity test has been appreciated as an useful laboratory method for selecting the optimal anticancer drug for solid carcinomas. Using human tumor xenografts, the correlation of in vitro and in vivo tests was studied. The sensitivity results were identical between the two methods for 75% of samples tested. In the other study, five surgically resected specimens were subjected to the in vitro test and were transplanted into nude mice. The in vitro tests were repeated on the xenografts, demonstrating satisfactory reproducibility of the sensitivity results.

The clinical significance of the scintillation assay (thymidine incorporation assay) which we developed was summarized as follows; 1)thymidine uptake by tumor cells which can be evaluated in each assay functioned as a significant predictor of prognosis of patients with gastric or colorectal cancer, 2)the tumor cell compartment in this assay system significantly increased more than did those in other culture systems, 3)evaluable rates were increased to more than 80% by introduction of the preculture system with collagen coated flasks, and 4)it can be considered that chemosensitivity testings may benefit for some types of human tumor, but not for all.

We analysed the relationship between several biological properties of gastric cancers and their chemosensitivity determined by MTT assay. Higher chemosensitivity was associated with poor differentiation, aneuploidy, and higher proliferative activity. Lymph node metastasis was more chemosensitive than primary lesion, while liver metastasis was less. Gastric cancer expressing multidrug-resistance associated protein (MRP) showed lower sensitivity to several anticancer drugs, including adriamycin and etoposide. p53 status and susceptibility to apoptosis were also associated with chemosensitivity. Thus, chemosensitivity of clinical gastric cancer might be increased if these characters can be modified by some new biologic therapy.

Meningioma is one of the popular benign brain tumors. However, the recurrence of this tumor is not infrequently encountered. In an attempt to establish the useful adjuvant therapy for the recurrent meningioma, in vitro chemosensitivity study for meningioma was conducted. Among various chemotherapeutic agents tested here, cisplatin showed highest cytotoxicity on cultured meningioma cells. In conclusion, cisplatin may be useful in adjuvant chemotherapy for the recurrent meningioma.

The many anticancer agents used in cancer chemotherapy possess either cytotoxic or cytocidal activity. However, since they do not have selective toxicity, they can injure not only the cancer cells but also the normal tissue and cells of the cancer patient. The severity of the damage caused to normal cells by these agents is largely dose-related, but the administration route and schedule also have a role. Each agent has a different pattern by which it affects the organs, tissues and cells. The damage these agents cause to normal cells is called side effects. The various complications which cause suffering in the patient and a markedly lower quality of life make treatment difficult. Many side effects have been reported. Some have clear causes, and their prevention and treatment are feasible in certain cases. However, there are still problems to be resolved. The incidence, causes, evaluation, severity, treatment and prevention are reviewed from the standpoint of the various side effects caused by the anticancer agents and the complications of the patient.

A 44 year-old woman with acute myeloid leukemia (AML, FAB, M4E) developed heart failure during treatment with anthracyclines for AML. She had not experienced heart disease and her left ventricular ejection fraction (LVEF) was 59% at the end of a successful remission induction therapy. Because her LVEF decreased to 33% after early consolidation therapy, the chemotherapy for AML was discontinued. The cumulative dose of daunorubicin, aclarubicin and mitoxantrone was 486 mg/m2, 135 mg/m2 and 55 mg/m2, respectively. In October 1990, four months after the end of the chemotherapy, heart failure (class III, NYHA) developed and did not improve by treatment consisting of dobutamin, digoxin and diuretics. Anthracycline cardiomyopathy was histologically confirmed by endomyocardial biopsy. Then we administered selective beta 1-antagonist, metoprolol (Seloken), with an initial dose of 5 mg/day which was doubled 3 times every 4 or 8 weeks to 40 mg/day, according to the treatment schedule of dilated cardiomyopathy. She recuperated satisfactorily (Class I, NYHA), and was discharged on February '91. Her LVEF gradually improved and it has been maintained at above 50% on an outpatient basis. The patient has been in complete hematological remission during this period. It seems that low dose selective beta 1-antagonist therapy has a potential to improve myocardial function in some patients with anthracycline cardiomyopathy.

The effect of granulocyte colony-stimulating factor (G-CSF) on neutropenia and infection was studied in a randomized trial in patients receiving intensive chemotherapy for acute leukemia. Fifty seven patients with acute leukemia (35 cases of refractory acute myeloid leukemia, 19 cases of acute lymphoblastic leukemia and 3 cases of blast crisis of chronic myeloid leukemia) were given G-CSF under either of the following two conditions; 1) Group A: starting G-CSF (200 micrograms/m2iv) administration 24 hrs after chemotherapy. 2) Group B: the same dose of G-CSF administration after a febrile episode of 38 degrees C with neutropenia (less than 1,000/microliters). Five patients were excluded from the study. Group A (27 patients) showed a shorter febrile period (2.15 +/- 2.98 days) than the 25 patients of Group B (3.40 +/- 4.78 days), but the difference was not statistically significant. Compared to Group B, Group A showed significantly early recovery of neutrophil counts as well as early recovery from documented infections. There was no evidence that early administration of G-CSF accelerates the growth of leukemic cells nor causes early relapse of acute leukemia.

Effects of an intravitreal injection of melphalan on the electroretinogram and on the retinal structure were studied in albino rabbits to establish the non-toxic dose for its intravitreal use. The a-wave, the b-wave, the c-wave, the oscillatory potential and the retinal structure remained unchanged after 10-micrograms injection, but moderately changed after 20-micrograms injection and greatly deteriorated after 90-micrograms injection. A 10-micrograms injection is equal to an intravitreal concentration of about 5.9 micrograms/ml, if evenly diffused in the rabbit vitreous. Considering that colony formation of in vitro retinoblastoma cells is completely suppressed by melphalan at 4 micrograms/ml concentration, an intravitreal application of melphalan could be used as a non-surgical treatment for retinoblastoma.

Fadrozole (CGS 16949 A, brand name: Afema) is an aromatase inhibitor developed firstly in Japan. This compound reduces estrogen levels in the body after administration, suppressing the growth of breast cancer. In animal experiments, this showed an inhibitory activity in vivo against estrogen-depended mammary tumor and the effect was potentiated by the combination of tamoxifen cytrate. In the domestic clinical trials against post-menopausal advanced-recurrent breast cancer, irrespective of the cases with ER positive or negative and even including pretreated cases, the compound showed response rate of 19.3%, the rate of long NC of 18.2%, and the total response rate of 37.5%. The prognosis of NC cases was similar to the effective (CR + PR) cases. The median survival time was 323.5 days which were better than the previous endocrine therapies. The side effects mainly consisted of nausea, vomiting, loss of appetite, abdominal pain, and fatigue, but these were all the level of grade 1. This compound-seemed to be a promising drug for the treatment of patients with post-menopausal breast cancer.

We developed a new in vitro assay for chemosensitivity test using collagen gel droplet embedded culture and image analysis. In this in vitro assay, we successfully minimized the cancer cell number required for culture to approximately 3-10 x 10(3) cells for each 30 microliters collagen gel droplet, obtained the sufficient growth of cancer cells using serum-free medium while suppressing the growth of fibroblastic cells, and measured the volume of cancer cells by eliminating the contaminating fibroblastic cells by an image processing technique. Anticancer effects of the in vitro assay showed a very good correlation with those of in vivo nude mouse assay using human cancer cell lines. The success rates of the in vitro assay for 141 surgical specimens of primary lung cancers and for 65 of primary breast cancers were 89 and 80%, respectively. The accumulated in vitro assay response rates of MMC, CDDP, VDS and VP-16 for primary lung cancers and of MMC, 5-FU and ADR for primary breast cancers were similar to the respective clinical response rates. These results suggest that this in vitro chemosensitivity test may be practically useful for clinical applications.

This clinical study was undertaken to examine intratumoral (i.t.) pharmacokinetics after intraarterial (i.a.) administration of MCNU (80mg/m2) in 5 patients with glioblastoma (GB) and 2 with anaplastic astrocytoma (AA). After resection or stereotactic biopsy of the cystic lesion, an Ommaya reservoir was placed into the tumor cavity in all patients. The distribution of MCNU in blood was compatible with a two-compartment model, and the half life of the alpha-phase and beta-phase was 4.1 minutes and 160.4 minutes, respectively. MCNU was detected in the i.t. fluid in 5 cases, 4 of GB and 1 of AA. The concentration of i.t. MCNU gradually increased during the 5 to 30 minutes after i.a. injection to a level about 20.0% of its blood concentration. However, no MCNU was detected in patients showing partial response (3 of GB and 1 of AA) or no change (1 of GB) after the i.a. infusion of MCNU during maintenance chemotherapy. These results suggests that MCNU may transfer into the tumor tissues. Further investigation is warranted.