Intra-arterial infusion chemotherapy has been applied for the treatment of malignant brain tumors to increase the distribution of the drug into the tumor. MX2, a new morpholinoanthracycline, is a lipophilic compound, and has a strong antineoplastic effect against human and rat glioma cells. In this report, the acute toxicity and distribution of MX2 after intracarotid injection were studied using female Wistar rats weighing 150 g. To test the acute toxicity, various doses ranging 1.5 to 6 mg/kg was administered. All rats died within 4 days when received more than 3 mg/kg of intra-arterial or intravenous MX2. No rats died if the dose was reduced to less than 2 mg/kg. For the purpose to examine distribution in the brain, rats which received 2 mg/kg of intra-carotid MX2 were killed 5 to 120 min. after injection. The level of MX2 in the ipsilateral brain tissue reached to the maximum 5 min. after injection, and then rapidly decreased. The maximum concentration of MX2 in the ipsilateral brain was 25-fold higher than that in the contralateral brain, and 20-fold higher than that after intravenous injection of the same dose. The AUC (area under the curve) in the ipsilateral brain after intra-carotid injection was 8.0-fold higher than that in the contralateral brain, and 7.3-fold higher than that after intravenous injection of the same dose. These results indicate that intra-carotid administration can increase the distribution of MX2 in the normal brain.

NIH3T3 cells transfected with c-H-ras and/or c-myc genes were examined for differences in drug sensitivity. The two transfectants used were NIH3T3-nm-1 (nm-1), pT22-3-nm-2. They were transfected with c-myc, c-myc plus activated c-H-ras, respectively. The relative resistances (IC50 values of transfectants/those of NIH3T3 cells) to cisplatin, adriamycin, 4-hydroperoxycyclophosphamide, melphalan, and CPT-11 were 2.1, 1.6, 4.7, 4.9, 1.6, respectively for nm-1 and 1.6, 2.2, 3.3, 9.1 and 2.2, respectively for nm-2. These results strongly suggest that the expression of the c-myc gene plays a role for the acquisition of drug resistance. The c-myc gene is believed to provide us an important clue for determining the mechanism of drug resistance.

Recent reports suggest that protein phosphorylation is involved in neural differentiation. We have found that specific inhibitors of protein phosphorylation at tyrosine residues, Erbstatin, Genistein, Herbimycin A, effectively induce neural differentiation in a human neuroblastoma cell line SK-N-DZ and a human medulloblastoma cell line Med-3, as indicated by the marked increase in the number of neurites/cell and in the expression of neurofilaments (160 k) detected by immunohistochemical studies. Possible involvement of protein phosphorylation at tyrosine residues in the differentiation of neural tumor cells was stressed.

A 74-year-old man with hepatocellular carcinoma developed cholangitis and bile lake in the liver after repeated TAI (anticancer drug-lipiodol suspension) and gelfoam TAE. Despite percutaneous transhepatic drainage, he died of hepatic failure 34 months after the first TAI and TAE. We speculate that cholangitis and bile lake were caused by chemical toxicity of highly concentrated anticancer drug to the bile duct and compression of the proximal bile duct by the tumor.

By means of 3 different kinds of in vitro chemosensitivity testings--(1) a nuclear damage assay developed by us, (2) MTT assay, and (3) colony formation inhibition assay--we examined the sensitivity of 8 kinds of human ovarian cancer cell lines to various anticancer drugs. The sensitivity of in vivo xenografts of the cell lines in nude mice to anticancer drugs was also examined by inhibition of the tumor growth. The in vitro--in vivo correlation of sensitivity was studied in respect to both sensitivity and specificity rates. 1. Different active anticancer drugs were screened among the 3 in vitro chemosensitivity testings in the same human ovarian cancer cell line. 2. The in vitro--in vivo correlation of the nuclear damage assay (sensitivity 50%, specificity 94%) was the highest among the 3 testings. The nuclear damage assay which we developed therefore seemed to be the most useful assay method for clinical use.

We performed an in vitro chemosensitivity test with 8 malignant brain tumor cell lines, which were established in our Department. It was shown that ACNU was moderately tumoricidal against only one cell (ONS-86) line. IFN-beta (interferon-beta) was more active against 4 cell (ONS-6, -20, -76, and -81) lines. VCR (vincristine), MTX (methotrexate), and Ara-C (cytosine arabinoside) and FK 973 were most effective against all 8 cell lines. There were some difference in the drug sensitivities among the tumors with the same pathological diagnosis. Since IFN-beta was tumoricidal against to the cells, co-culture of IFN-beta and one of other antitumor agents seemed to induce more antitumor effects. With regard to the side effects of IFN-beta, the combined therapy with IFN-beta and other drugs induced more antitumor effects against malignant brain tumor cells and seemed to reduce the side effects.

Tegafur and UFT are most widely used for the treatment of cancers of the gastrointestinal tract. FdUMP, a metabolite of 5-fluorouracil(5-FU), is known to have an inhibitory activity of thymidylate synthase (TS). We administered 600 mg/day of tegafur or UFT to 37 patients with cancer of the large bowel beginning 1 week prior to surgery and then measured the concentrations of tegafur and 5-FU, and TS inhibition rate in the excised tissue. Our results showed that the concentrations of 5-FU in tumor were 0.077 +/- 0.026 microgram/g in tegafur group and 0.208 +/- 0.143 microgram/g in UFT group, with the UFT showing significantly higher levels (p less than 0.05). On the other hand, TS inhibition rates in tumor tissue were 45.5 +/- 13.3% in tegafur group and 56.1 +/- 13.0% in UFT group, with a significantly higher level existing in the latter group (p less than 0.05). Furthermore, the same high 5-FU concentration and TS inhibition rates were observed in the lymph nodes affected by metastasis. No difference between the tegafur and UFT groups was noted in normal tissue or normal lymph nodes, and compared to tegafur, UFT showed an effective action on cancerous large bowel tissue.

A chemosensitivity test was carried out on superficial bladder cancers using the trypan blue dye exclusion assay for the purpose of screening chemosensitive drugs for intravesical chemotherapy. Transplantable murine bladder tumor cells (MBT-2) were incubated, in vitro, in the presence of adriamycin (4, 40, 400, 1000 micrograms/ml) as well as verapamil (3, 30, 100, 500 micrograms/ml) at 5% CO2, 37 degrees C for two hours. After cellular viabilities were calculated, MBT-2 cells were inoculated into the hind limbs of mice. The cellular viability was correlated well with the ratio of tumor appearance, tumor growth inhibition and prolongation of survival, and was dose dependent in the adriamycin treated groups. On the other hand, a reduction of cellular viability, tumor growth inhibition and prolongation of survival were seen in the high dose verapamil (100, 500 micrograms/ml) treated groups. Human superficial bladder cancer cells were incubated in the presence of adriamycin, 4'-0-tetrahydropyranyladriamycin, mitomycin C and pepleomycin (1000 micrograms/ml) and/or verapamil (500 micrograms/ml). The reduction rates of cellular viability markedly varied with the kind of anticancer drugs. A reduction of cellular viability of human tumor cells as well as MBT-2 cells was seen in the verapamil treated groups. This rapid and handy assay seems to be useful for the purpose of screening chemosensitive drugs for intravesical chemotherapy.

HO-221, N-[4-(5-bromo-2-pyrimidinyloxy)-3-chlorophenyl]-N'-(2- nitrobenzoyl) urea is a new benzoylphenylurea derivative. The compound exhibits significant antitumor effects against various animal tumors, and was especially effective against the solid tumors implanted subcutaneously. HO-221 inhibits DNA polymerase alpha activity strongly in vitro. In this study, we examined the cross-resistance of HO-221 to various antitumor agents using sublines of mouse leukemia. HO-221 showed antitumor effects in mice bearing L 1210 or P 388 leukemia resistant to 10 antitumor agents, DM (daunomycin), MMC (mitomycin C), CDDP (cisplatin), 5-FU (5-fluorouracil), Ara-C (cytosine arabinoside), MTX (methotrexate), CPA (cyclophosphamide), CQ (carboquone), ADM (adriamycin) and VCR (vincristine), respectively. These antitumor agents were also effective in P 388 leukemia resistant to HO-221 (P 388/HO-221). Furthermore, CDDP- and MMC-resistant sublines showed a collateral sensitivity to HO-221 in vivo. The grow the inhibitory effects were also noted in vitro in ADM-, CDDP- and MMC-resistant cells by HO-221. However, the in vitro experiments didn't show such collateral sensitivity on the resistant sublines. These results suggest that there is no cross-resistance between HO-221 and other known antitumor agents, and that HO-221 seemed to be worth for evaluating clinical usefulness.

We evaluated the usefulness of in vitro human tumor culture system using a specialized collagen gel matrix derived from pigskin as a chemosensitivity test for human gastric cancer including scirrhous type. Seven xenograft tumors derived from human gastric cancers were examined with this system and compared with the data obtained by the nude mouse chemosensitivity assay. Xenograft tumors exhibited an in vivo like three-dimensional growth on the collagen gel matrix. There were very close associations between the results obtained by this assay and those obtained from the same drug by the nude mouse assay. Moreover, this system seemed to be useful for prediction of drug sensitivity for scirrhous type gastric cancers. This in vitro assay system has an advantage for chemosensitivity test, because of its convenience, rapidity, and in vivo like three-dimensional tumor growth.

The closed relationship between nasopharyngeal carcinoma (NPC) and Epstein-Barr virus (EBV) has been pointed out. However, it still remains unclear whether the EBV becomes a true factor in initiation and promotion in NPC or not, because of difficulty to establish this cancer strain. We succeeded to establish the EBV-genome positive cell line (NPC-TY861) in 1986, which had been derived from the tissues of nasopharyngeal carcinoma. In this study, the characteristics of this cell strain were investigated by tests for sensitivity against several kinds of anti-cancerous agents and immuno-activated cells. The sensitivity tests revealed that NPC-TY861 cell line was extremely sensitive to PEP, ADR, VCR, LPA and CDDP with dose dependent manner. Furthermore, this cell strain had similar sensitivity to CDDP derivatives, such as 254-S, NK121, DWA2114R and CBDCA as KB cell strain did, which had been derived from an oral base cancer. The oral base cancer was a poorly differentiated squamous cell carcinoma histopathologically as same as NPC-TY861 cell strain. On the other hand, NPC-TY861 cell strain showed no sensitivity to cytokines, TNF and IFN, which have direct anti-cancerous actions. NPC-TY861 cell strain had resistant to NK cells and much more resistant to LAK cells derived from IL-2 than Daudi cell strain did. In order to elucidate the oncogeneous mechanism in NPC, it is indispensable to study the character of this cell strain and it would promise to get a new effective therapeutic method for the patient with NPC, who has bad prognosis.

Inhibitory effects of anthracyclines on bacterial collagenase were examined. Daunomycin, doxorubicin, and aclarubicin potently inhibited the collagenase, but mitomycin C and 5-fluorouracil did not inhibit. Inhibitory activities of anthracyclines were constant regardless of the concentrations of Ca2+, activator of collagenase, or of Zn2+, active center of collagenase. These results suggest that the inhibitory mechanisms of anthracyclines were independent of a chelate effect on Ca2+ or Zn2+.

Recently, high aged patients with malignancies have increased in number. When cancer chemotherapy is applied for the high aged patients, kinds or doses of anti-cancer drugs must be more carefully selected or decided than for younger patients, because it is said that the side effects of anti-cancer drugs would easily induce irreversible organ disorders and death in high aged patients. The effects of cancer chemotherapy were compared between high aged patients (over 75 years) and younger patients (5 decade years) with special reference to side effects. The patients underwent cancer chemotherapy were 79.7% of high aged patients and 93.6% of younger. The reasons why cancer chemotherapy was not carried out were high age (5.6% of high aged patients), poor general conditions (7.0% in high aged, 2.3% in younger) and post operative complications (7.0% in high aged, 3.2% in younger). The proportion of patients suffered side effects was almost same in both groups. Dead cases caused by side effects of anti-cancer drugs were 5 in high aged patients (4.4%) and 7 in younger (3.4%). The reason why the proportion of side effects in both groups was not different was that the doses of anti-cancer drugs given for high aged patients were reduced to 80-90% of those for younger patients.

To establish the combination of chemotherapy with adoptive immunotherapy (AIT), using lymphokine activated killer cells (LAK) and/or interleukin-2 (IL-2), author examined the following: 1) Pretreatment with anticancer agents for peripheral blood mononuclear cells (PBMC) and its effect on LAK cell cytotoxicity and cell yield. 2) The addition of anticancer agents in the induction phase to LAK cell and its effect on LAK cell cytotoxicity and cell yield. 3) Pretreatment with anticancer agents to induced LAK cell and its effect on LAK cell cytotoxicity and cell yield. 4) The cytotoxicity of LAK cell against tumor cells treated with anticancer agents. Our experiment has shown that when we take peripheral blood mononuclear cells (PBMC) to induce LAK cells, there is no influence on its LAK cell yield or its cytotoxicity after being harvested as LAK cells, even if there is a maximum concentration of anticancer agents, but in the case of the LAK cell induction phase VDS, CDDP, ADM and MMC have a significant effect on LAK cell yield and on cytotoxicity of LAK cell after being harvested as LAK cells. And it has also been shown that, if there is a maximum concentration of anticancer agents, it has an effect on the induced LAK cell cytotoxicity and on the LAK cell yield after being recultured with IL-2. On the other hand, LAK cell cytotoxicity makes no difference to tumor cells whether they are treated or not with anticancer agents. These results suggest that we can take peripheral blood mononuclear cells to induce LAK cells unrelated to the administration of anticancer agents, and that if we use a combination of chemotherapy with adoptive immunotherapy (IL-2 administration and/or LAK cell adaptation), we should start with the administration of anticancer agents and then administer IL-2 and/or transfer LAK cells after the concentration of anticancer agents decreased under 1/10 of maximum concentration in the blood level of our conventionally clinical use.

The marrow granulocyte reserve (MGR) of patients with lung cancer have been estimated by measuring the maximum neutrophil increment after administration of hydrocortisone. The MGR was found to have decreased in four of 19 untreated patients, but the reason for this decrement was not clear. Further, there were no differences in the MGR between the cell types or cancer stages. The MGR in patients 70 years old or older tended to be decreased. After chemotherapy or radiation therapy, the MGR depressed significantly. However, on administration of OK 432, the MGR significantly increased in two patients who had received radiation therapy and whose MGR had been deficient initially.

Phase II study of YNK01 (1-beta-D-arabinofuranosylcytosine-5'-stearylphosphate), a derivative of cytosine arabinoside, on hematological malignancies was conducted by multi-institutional cooperative group. YNK01 was administered orally at dose of 100-300 mg/body/day for more than 2 weeks. The number of registered and evaluated patients were 211 and 156, respectively. Of 23 patients with acute myelogeneous leukemia (AML), 2 complete response (CR), one partial response (PR) were observed (CR + PR: 13.0%). Hypoplastic leukemia (1/4: 25%), acute unclassified leukemia (1/1: 100%). Of 45 patients with MDS, 2CRs, 6 good response (GR) and 5PRs were observed (CR + PR: 28.9%). AML developing after a prior history of MDS (5/17: 29.4%), CML-BC (2/9: 22.2%). Of 19 patients with CML, 9 achieved CR, 3 achieved PR (63.2%). Of 11 patients with polycythemia vera, 4 achieved CR, 5 achieved PR (81.8%). Of 6 patients with essential thrombocytosis, 2 achieved CR, one achieved PR (50%). The major adverse effects included gastrointestinal toxicities such as nausea, vomiting, anorexia, diarrhea, and elevation of GOT and GPT which were tolerable and reversible. This study indicates that YNK01 is a useful agent against acute leukemia and MDS, especially RAEB, RAEB in T, CMMoL.

Chemotherapeutic treatment for cancer has been successful in prolonging survival but it has also been demonstrated that survivors of cancer patients who had received chemotherapy with alkylating agents have an increased risk of second malignancies, mostly acute non-lymphatic leukemia. The purpose of this paper is to show practical problems pertaining to the development and clinical use of anticancer agents in terms of prevention of second cancers.

Harvest of peripheral blood stem cells (PBSC) for autografts is a safe, reliable procedure with low morbidity in children with cancer, and cryopreserved PBSC are useful in reducing cytopenia following marrow-ablative chemotherapy. The colony forming unit granulocyte/macrophage (CFU-GM) content of the thawed grafts is an important determinant of hematopoietic recovery after PBSC autografts. The possible value of high-dose chemotherapy without total body irradiation and PBSCT compared to intensified chemotherapy in the treatment of children with very high-risk lymphoid malignant disorders was reported.