Some of organ dysfunctions due to cancer therapy in children are common to those of adults, but others are specific for children. Even common toxicities may have aspects peculiar to children. For example, cisplatin nephrotoxicity easily causes hypomagnesemic, hypocalcemic tetany in children which is rare in adults. Occurrence of second primary malignancies is serious late effect of cancer therapy. Concerning this problem two factors are important in children. Firstly, children with heritable embryonal cancers are predisposed to develop additional malignancies related and unrelated to therapy. Secondly, proportion of different parts of body of children is different from one of adults and normal tissues distant from the primary radiation field may receive surprisingly large dose of irradiation. For example, a 8-year-old boy received 6 to 9% of dose of prophylactic skull irradiation for acute lymphocytic leukemia to his thyroid. Younger children who have smaller viscerocranium are expected to have larger dose. Children who received antileukemic therapy for 3 to 7 years showed significant delays of linear growth and bone age.

A total of 71 cases with primary brain tumors (44 cases) and metastatic brain tumors (30 cases) were entered into our clinical studies with MCNU and radiation therapy or MCNU alone. With regard to tumor reduction on CT scan, the response rates obtained for MCNU and radiation were 21.7% for malignant gliomas and 50.0% for metastatic brain tumors. With regard to improvement of neurological signs, the response rates obtained for MCNU and radiation were 62.9% for malignant gliomas and 71.4% for metastatic brain tumors. The response rates for MCNU were 5.8% for malignant gliomas and 46.1% for metastatic brain tumors. In the improvement of performance status, the response rates for MCNU and radiation were 51.8% for malignant gliomas and 64.2% for metastatic brain tumors. The response rates for MCNU were 46.1% for malignant gliomas and 30.7% for metastatic brain tumors. A minimal degree of hematological toxicity occurred but this gradually disappeared. These results suggested that MCNU has relatively effective antitumor activity against metastatic brain tumors and an enhanced effect with radiation against malignant gliomas.

The human tumor clonogenic assay (HTCA) and the human tumor xenograft system implanted in nude mice were performed simultaneously in an ovarian cancer patient as chemosensitivity testing. Eight anticancer drugs (5-FU, MMC, VCR, ACD, BLM, VLB, CDDP, and ADM) were applied to the HTCA and the human tumor xenograft system. In the HTCA, 5-FU and MMC were sensitive, VCR was moderately sensitive, and ACD, BLM, VLB, CDDP, and ADM were resistant. In the human tumor xenograft system, MMC, VCR, and ADM showed tumor regression (++), and CDDP, VLB, BLM, 5-FU, and ACD exhibited no response (-). Two of the three drugs, which were classified as sensitive or intermediately sensitive in the HTCA, showed tumor regression (++) in the human tumor xenograft system. And four of the five drugs, which were resistant in the HTCA, exhibited no response (-) in the human tumor xenograft system. Clinically, PVB therapy (CDDP, VLB, and BLM) was applied to the present patient, but after recurrence, 5-FU + MMC therapy was applied on the basis of the results of the HTCA. In addition, ADM was added with reference to the results of the human tumor xenograft system. As a result of this therapy, the tumor growth was inhibited. It is possible from the present data that simultaneous chemosensitivity testing of the HTCA and the human tumor xenograft system implanted in nude mice is very useful when choosing sensitive anticancer drugs.

A growing interest has been shown in antiemetics with important advances in understanding the physiology of vomiting and the development of new anticancer agents having high emetic potential such as cisplatin. At present, high-dose metoclopramide, dexamethasone and butyrophenones have shown effective antiemetic action. In addition, antiemetic drug combinations that affect more than one neurotransmitter receptor have achieved improved emesis control. While improvements have been made in acute chemotherapy-induced emesis, anticipatory and delayed emesis is still a difficult problem. Further studies under well-designed trials are necessary to establish which of the available agents, doses, routes of administration, and schedules are best for reducing emesis depending on the chemotherapeutic drugs used.

There is a need for chemosensitivity tests of human tumors to become simpler and to have a better correspondence with their therapeutical record. We examined and compared two chemosensitivity tests in vitro. One was a clonogenic assay performed using a double agar system and the other was a novel dye exclusion method that was a modification of the traditional dye exclusion method of Weisenthal. Cultured cells and surgical speciners of urogenital tumors were used for the present experiments. Comparison of chemosensitivity between the clonogenic assay and the novel dye exclusion test resulted in a similar dose response for each, and both tests were suitable not only for cultured cells but also surgical speciners. Among surgical speciners, 17 of 25 cases (68%) tested by clonogenic assay and 8 of 11 cases (73%) tested by novel dye exclusion test were successful in detecting drug sensitivity. Renal cell carcinomas had higher plating efficiency and showed a higher success rate in the clonogenic assay than any other urogenital tumors. On the other hand, the novel dye exclusion method depended on tumor cell growth in suspension culture. Among 11 cases on which both the clonogenic assay and the novel dye exclusion method were performed, only in one case was there failure to estimate drug sensitivity. Therefore, more successful results in examining the chemosensitivity of urogenital tumors might be expected by using both the clonogenic assay and the novel dye exclusion method.

The purpose of this paper is to analyze the available data on SM-108 (4-carbamoylimidazolium 5-olate) with respect to its clinical usefulness, optimal method of administration, and side effects. Successful remission induction was achieved in atypical leukemia using low dose SM-108. To analyze the action of SM-108, freshly isolated leukemic cells and cells from human leukemic cell line were cultured in the presence of SM-108. Minimal evidence of differentiation induction was observed. SM-108 in a higher dose, alone or in combination with other drugs was advocated for the treatment of adult ALL. Side effect including myelotoxicity and gastrointestinal toxicity was minimal.

590-S (1-phthalidyl-5-fluorouracil) is a derivative of 5-fluorouracil and shows a several characteristics in experimental studies. That is, good absorption from the intestine, high blood levels of 5-fluorouracil, its rapid clearance, low toxicities, excellent tumor inhibition and broad anticancer spectrum, etc. From preliminary studies and phase I studies, MTD is thought to be 750-800 mg/m2 in daily administration. Mild G.I. toxicities was encountered in a few cases. However, CNS toxicities were not experienced in any of our cases.

The properties of Porphyrin and Pheophorbide derivatives with cyclic tetrapyrrole structure have a specific character to accumulate selectively in tumor tissues and destruct tumor cells by photodynamic action. Recently, Photoradiation therapy of cancer with Porphyrin derivatives has put into practice, but its indication is very limited. We examined fundamentally on tumor tissue affinity of various Porphyrin and Pheophorbide derivatives, aiming at expanding therapeutic indication and application. As materials we used 73 derivatives in total, including 14 Porphyrin derivatives, 32 Pheophorbide derivatives, 17 Porphyrin metal complex and 10 Pheophorbide metal complex, and examined about the relation between their side branches and their tumor tissue affinity by N2-pulsed Laser spectrofluorometry, using tumor-bearing Golden Hamster. Furthermore, we investigated substances connected with Hematoporphyrin derivatives (HPD) in tumor cells. As a result, we had the following conclusions. N2-pulsed Laser spectrofluorometry is useful for analysis of Porphyrin and Pheophorbide derivatives in vivo. In Porphyrin derivatives, those with dimer structure and acetyl radical have higher tumor tissue affinity than those without such structures. Existence of OH radical and dimer structure is dispensable for tumor tissue affinity of Pheophorbide derivatives. OH radical in Porphyrin metal complex and acetyl radical in Pheophorbide metal complex are important factors for tumor tissue affinity of them. It is suggested that Hematoporphyrin derivatives (HPD) in vivo combine with protein in tumor cells.

In vitro tests were performed to assess the sensitivity to six anticancer agents-ACT-D, ADM, CDDP, CQ, 5-FU and MMC-of a JOHYL-1 (ascites type) cell line from human dysgerminoma which was used as challenge strain. For comparative assessment, anticancer sensitivity was expressed as the ratio of IC50 and IC90 to LD50 (i.v.) in mice. Drug dose-response and time-response curves were plotted, and the IC50 ratio was calculated, for each test compound in order to investigate the mechanism of anticancer action. The results obtained were as follows. CQ proved to be remarkably active and ADM fairly active against JOHYL-1 (ascites), but 5-FU, CDDP and MMC varied remarkably with the parameter of measurement employed. Analysis of IC50 ratio data and patterns of cell growth inhibition indicated the growth-inhibitory effect of CDDP to be concentration-and time-dependent. The results of the present study are in close accord with the pattern of action reported in the literature.

5'-Deoxy-5-Fluorouridine is converted to 5-Fluorouracil by pyrimidine nucleoside phosphorylase of which activity is higher in tumor tissues than in surrounding normal ones. The interim result of the phase II study of this drug showed an efficacy in breast, gastric, colorectal and head & neck cancers. Above all, some CR cases in breast cancer indicated remarkable superiority of this drug for monotherapy. The duration of response was relatively long. Even in the cases with previously negative fluorinated pyrimidine therapy, this drug showed a considerable response rate. The main side effect was diarrhea but it was controllable. Diarrhea would become a good indication for determining continuation or cessation of the treatment with this drug.