Prognostic impact of FOXF1 polymorphisms in gastric cancer patients.

A recent genome-wide association study identified seven single-nucleotide polymorphisms (SNPs) in region 16q24, near the Forkhead box-F1 (FOXF1) gene, which confer susceptibility to esophageal adenocarcinoma. We examined whether these SNPs are associated with clinical outcomes in gastric cancer (GC) patients in Japan and the United States. A total of 362 patients were included in this study: 151 Japanese GC patients treated with first-line S1 plus CDDP (training cohort) and 211 GC patients from Los Angeles County (LAC; validation cohort). Genomic DNA was isolated from whole blood or tumor tissue and analyzed by PCR-based direct DNA sequencing. Cox proportional hazard regression analyses were used to assess relationships between FOXF1 SNPs and progression-free survival (PFS) and overall survival (OS). FOXF1 rs3950627 was significantly associated with survival in both the training and validation cohorts. Japanese patients with the C/C genotype had a longer PFS (median 8.2 vs 5.3 months, hazard ratio (HR) 1.44, P=0.037) and OS (median 16.4 vs 12.2 months, HR 1.44, P=0.043) compared to patients with any A allele. Similarly, LAC patients with the C/C genotype had improved OS (3.9 vs 2.3 years, HR 1.5, P=0.022). Subgroup analyses showed these associations were specific to male patients and primary tumor subsite. Our findings suggest that FOXF1 rs3950627 might be a promising prognostic marker in GC patients.

CXCR4 polymorphism predicts progression-free survival in metastatic colorectal cancer patients treated with first-line bevacizumab-based chemotherapy.

We analyzed associations between CXCR4/CXCL12 single-nucleotide polymorphisms and outcomes in metastatic colorectal cancer (mCRC) patients who underwent first-line bevacizumab-based chemotherapy. A total of 874 patients were included in this study: 144 treated with bevacizumab and FOLFOX or XELOX (training cohort), 653 treated with bevacizumab and FOLFIRI or FOLFOXIRI (validation cohort A or B) and 77 treated with cetuximab- and oxaliplatin-based regimens (control cohort). One CXCR4 polymorphism (rs2228014) and two CXCL12 polymorphisms (rs1801157 and rs3740085) were analyzed by PCR-based direct sequencing. Patients with a C/C genotype had a prolonged progression-free survival (PFS) compared with those with any T allele (P=0.030) in the training cohort. Similarly, patients with the C/C genotype had a superior PFS in the validation cohorts, but not in the control cohort. Our findings suggest that a common genetic variant, CXCR4 rs2228014, could predict PFS and may guide therapeutic decisions in mCRC patients receiving first-line bevacizumab-based chemotherapy.

Dose-finding phase I study of simultaneous weekly infusion with doxorubicin and docetaxel in patients with advanced breast cancer.

BACKGROUND: Combination therapy with doxorubicin (DOX) and docetaxel (DOC), given 3 weeks apart, is one of the standard regimens used for treating metastatic breast cancer, but it frequently generates febrile neutropenia. To find a safer regimen with less myelotoxicity and the appropriate dose intensity, we conducted a phase I study of simultaneous weekly infusion with DOX and DOC. METHODS: Twenty-five patients with advanced breast cancer were treated with an intravenous push-injection of DOX that was immediately followed by a 1-h infusion of DOC. This was repeated every week for at least 6 weeks. The premedication employed was three 4-mg doses of dexamethasone every week. Patients were divided into four groups for which the doses of DOX and DOC were escalated in 5-mg/m2 increments. RESULTS: In the 18 patients who were treated with DOX 15 or 20 mg/m2 and DOC 25 mg/m2, or lower, the regimen was found to be tolerable, without febrile episodes. The regimen with 20 mg/m2 of DOX and 30 mg/m2 of DOC was the maximum tolerated dose. Other indications of grade 3 toxicity included asthenia in 4% of patients, anorexia in 8%, and vomiting in 8%. Of the 25 patients, 14 had a partial response. The overall response rate was 56% (95% confidence interval [CI], 35% to 77%). The recommended dose for further trial was 20 mg/m2 of DOX and 25 mg/m2 of DOC. CONCLUSION: Simultaneous weekly infusion with DOX and DOC was feasible, with modest neutropenia and preserved dose intensity. This regimen may be helpful in the management of patients with advanced breast cancer.

In vitro selection of an RNA sequence that interacts with high affinity with thymidylate synthase.

Previous studies have shown that the repressive effect of thymidylate synthase (TS) mRNA translation is mediated by direct binding of TS itself to two cis-acting elements on its cognate mRNA. To identify the optimal RNA nucleotides that interact with TS, we in vitro synthesized a completely degenerate, linear RNA pool of 25 nt and employed in vitro selection to isolate high affinity RNA ligands that bind human TS protein. After 10 rounds of selection and amplification, a single RNA molecule was selected that bound TS protein with nearly 20-fold greater affinity than native, wild-type TS RNA sequences. Secondary structure analysis of this RNA sequence predicted it to possess a stem-loop structure. Deletion and/or modification of the UGU loop element within the RNA sequence decreased binding to TS by up to 1000-fold. In vivo transfection experiments revealed that the presence of the selected RNA sequence resulted in a significant increase in the expression of a heterologous luciferase reporter construct in human colon cancer H630 and TS-overexpressing HCT-C:His-TS+ cells, but not in HCT-C18 cells expressing a functionally inactive TS. In addition, the presence of this element in H630 cells leads to induced expression of TS protein. An immunoprecipitation method using RT-PCR confirmed a direct interaction between human TS protein and the selected RNA sequence in transfected human cancer H630 cells. This study identified a novel RNA sequence from a degenerate RNA library that specifically interacts with TS.

Pilot study of continuous low-dose 5-fluorouracil and cisplatin (FP regimen) for the treatment of metastatic breast cancer.

Background. The effect of low-dose 5-fluorouracil (FU) and cisplatin therapy (FP regimen) against metastatic breast cancer was investigated. Methods. A pilot study of the FP regimen was performed in 11 patients with metastatic breast carcinoma who had previously received chemotherapy, including adriamycin, and/or hormonal therapy. Their median age was 56 years (range, 48-72 years). Visceral metastases were present in all patients. FU, at a dose of 170 mg/m(2) per day, was administered for 28 days by continuous intravenous infusion. Cisplatin (7 mg/m(2) per day) was given intravenously on days 1-5, 8-12, 15-19, and 22-26. After a 2-week interval, this treatment was repeated. Results. Of the 11 patients assessable for tumor response to the FP regimen, 4 patients (36%; 95% confidence intervals [CI], 8%-64%) achieved an objective response, with 1 showing a complete response and 3 showing a partial response. Median time to progression was 6.5 months (range, 4-25 months). The median survival time from the initiation of the FP regimen was 11 months (range, 3-25 months). Gastrointestinal and hematologic toxicity was mild. Conclusion. The FP regimen is promising for and has acceptable tolerance in patients with metastatic breast carcinoma refractory to previous anthracycline-containing chemotherapy.

Thymidylate synthase protein and p53 mRNA form an in vivo ribonucleoprotein complex.

A thymidylate synthase (TS)-ribonucleoprotein (RNP) complex composed of TS protein and the mRNA of the tumor suppressor gene p53 was isolated from cultured human colon cancer cells. RNA gel shift assays confirmed a specific interaction between TS protein and the protein-coding region of p53 mRNA, and in vitro translation studies demonstrated that this interaction resulted in the specific repression of p53 mRNA translation. To demonstrate the potential biological role of the TS protein-p53 mRNA interaction, Western immunoblot analysis revealed nearly undetectable levels of p53 protein in TS-overexpressing human colon cancer H630-R10 and rat hepatoma H35(F/F) cell lines compared to the levels in their respective parent H630 and H35 cell lines. Polysome analysis revealed that the p53 mRNA was associated with higher-molecular-weight polysomes in H35 cells compared to H35(F/F) cells. While the level of p53 mRNA expression was identical in parent and TS-overexpressing cell lines, the level of p53 RNA bound to TS in the form of RNP complexes was significantly higher in TS-overexpressing cells. The effect of TS on p53 expression was also investigated with human colon cancer RKO cells by use of a tetracycline-inducible system. Treatment of RKO cells with a tetracycline derivative, doxycycline, resulted in 15-fold-induced expression of TS protein and nearly complete suppression of p53 protein expression. However, p53 mRNA levels were identical in transfected RKO cells in the absence and presence of doxycycline. Taken together, these findings suggest that TS regulates the expression of p53 at the translational level. This study identifies a novel pathway for regulating p53 gene expression and expands current understanding of the potential role of TS as a regulator of cellular gene expression.

Epirubicin-containing high-dose chemotherapy followed by autologous hematopoietic progenitor cell transfusion for patients with chemotherapy-sensitive metastatic breast cancer: results of 5-year follow-up.

PURPOSE: Conventional chemotherapy for metastatic breast cancer results in very few long-term survivors. With a view to overcoming this problem, we hypothesized that a higher rate of complete response (CR) would lead to more long-term survivors. Therefore, we conducted a phase II study of epirubicin-containing high-dose chemotherapy (HDC) followed by autologous hematopoietic progenitor cell transfusion in patients who were sensitive to induction chemotherapy. METHODS: The induction chemotherapy consisted of doxorubicin 60 mg/m2, cyclophosphamide 750 mg/m2 and fluorouracil 750 mg/m2 on day 1. Supported by G-CSF, this chemotherapy was repeated for at least three cycles at intervals of 2 weeks until the achievement of > 50% tumor regression. The HDC comprised epirubicin 120 mg/m2 on day 1, cyclophosphamide 60 mg/kg on days 1 to 3 and thiotepa 6 mg/kg on days 1 to 3, followed by autologous bone marrow transplantation and peripheral blood stem cell transfusion. RESULTS: Of 25 patients who achieved a partial response to the induction chemotherapy, 17 were treated with the HDC. Of the 15 patients evaluable for response, 10 achieved a CR (67%), giving an overall CR rate of 43% (10/25). The disease-free survival rate at 5 years was 27%. The median duration of overall survival was 21 months and the overall survival rate at 5 years was 31%. However, the survival curves were not significantly different from those of the historical controls who achieved a CR or PR to conventional chemotherapy. There were three early deaths, one as a consequence of disease progression and two treatment-related (sepsis and heart failure). Diarrhea (grade 3, 76%) and stomatitis (grade 3-4, 29%) were the dose-limiting toxicities. CONCLUSIONS: The present study suggests that epirubicin-containing HDC is able to induce a high rate of CR, but its benefit in terms of survival is still unclear. To determine whether HDC can achieve a cure in some patients, further studies in a larger number of patients, with a longer follow-up, are necessary.

[Effective and low toxicity chemoradiotherapy for distant metastatic esophageal cancer].

A sixty-seven-year-old male who had T4N4M1 (stage IV) advanced esophageal cancer with bilateral pulmonary and multiple lymph-node metastases received 1-hr drip intravenous infusions of low-dose cisplatin (CDDP) at 7 mg/m2 on Days 1-5, 8-12, 15-19, and 22-26, protracted intravenous infusions of 5-fluorouracil at 200 mg/m2 on Days 1-28, and X-ray therapy of 2 gray/fraction x 5 fractions/week (total 40 Gy; LDFPX therapy). XRT was also administered alone (total 60 Gy). After 1 course of LDFPX therapy, the primary and multiple lymph node metastases responded completely. The bilateral pulmonary metastases were remarkably reduced in size and performance status improved. After that we tried low dose CDDP 10 mg/body twice a week and UFT 600 mg/body (LDP + UFT therapy) on an outpatient basis. Especially, bilateral pulmonary metastases were more reducing tumor size by LDP + UFT therapy. These treatments had a therapeutic effect and very low toxicity. This chemotherapy is thought to be effective against advanced esophageal cancer.

Vesicular anthracycline accumulation in doxorubicin-selected U-937 cells: participation of lysosomes.

The U-A10 cell line, a doxorubicin-selected variant of human U-937 myeloid leukemia cells, exhibits a redistribution of anthracyclines into a expanded vesicular compartment. The acidic nature of this compartment was confirmed by vital staining with a pH sensitive dye, LysoSensor yellow/blue DND-160. Identification of the vesicular compartment was performed by immunofluorescence analysis. Staining for the LAMP-1 and LAMP-2 antigens showed that the vesicles are enlarged lysosomes that are eccentrically placed near the nucleus of U-A10 cells. By contrast, the expression of the multidrug resistance-associated protein and the P-glycoprotein was observed predominately on the plasma membrane of the drug-resistant cells. The accumulation of daunorubicin into cellular compartments was quantified using radiolabeled drug. Exposing cells to 3[H]-daunorubicin and then isolating intact nuclei showed that nuclei from U-A10 cells accumulated twofold to threefold less anthracycline than nuclei from U-937 cells. However, when nuclei were isolated first and then exposed to 3[H]-daunorubicin, little difference in net nuclear drug accumulation was detected. Cytoplasts prepared from U-A10 and U-937 cells were exposed to 3[H]-daunorubicin to measure cytoplasmic drug accumulation. At external daunorubicin concentrations of 100 ng/mL or higher, cytoplasts from U-A10 cells accumulated significantly more daunorubicin than cytoplasts from U-937 cells. Moreover, studies with the lysosomotropic agent chloroquine showed that U-A10 cells accumulated twofold more chloroquine and showed twofold enhanced sensitivity to this agent as compared with parental U-937 cells. Fluorescence microscopy showed that chloroquine affects vesicular anthracycline sequestration in U-A10 cells with an associated increase in daunorubicin nuclear fluorescence. Although chloroquine did not alter anthracycline cytotoxicity in parental cells, it restored daunorubicin and doxorubicin sensitivity to U-A10 cells. Taken together, these studies demonstrate that U-A10 cells exhibit a redistribution of the lysosomal compartment. The trapping of drug into an expanded acidic vesicular compartment results in decreased nuclear drug accumulation and decreased cytotoxicity. Lysosomotropic agents, such as chloroquine, warrant further study as modulators of this acquired drug-resistance phenotype.

Expression of the multidrug resistance associated protein and P-glycoprotein in doxorubicin-selected human myeloid leukemia cells.

Drug-resistant sublines of the human U-937 myeloid leukemia cell line were selected in doxorubicin concentrations of 10, 40, and 200 ng/mL (designated U-A10, U-A40, and U-A200, respectively). Northern blot analysis showed overexpression of the multidrug resistance-associated protein (MRP) gene, but not MDR1, in U-A10 cells as compared with parental U-937 cells. Prolonged passage of U-A10 cells in 10 ng/mL of doxorubicin had little effect on MRP RNA levels, but increased MDR1 expression. The U-A40 and U-A200 cells, derived by selection of U-A10 cells, showed high levels of both MRP and MDR1 expression. None of the drug-resistant cell lines showed MRP or MDR1 gene amplification as judged by Southern blot analysis. U-A10 cells exhibited minimal decreased net accumulation of anthracycline, whereas U-A40 and U-A200 cells showed more significantly decreased drug accumulation as compared with U-937 cells. Subcellular anthracycline accumulation in U-937 cells as determined by fluorescence microscopy showed daunorubicin fluorescence predominately in the nucleus. However, the drug-resistant cell lines showed minimal nuclear drug accumulation with marked redistribution of drug into a vesicular compartment. Treatment with sodium azide/2-deoxyglucose, 2,4-dinitrophenol, or monensin, but not verapamil, abolished the vesicular accumulation. These studies in doxorubicin-selected U-937 cells indicate that induction of MRP overexpression occurs before that for the MDR1 gene. In addition, the drug-resistant cells possess an energy-dependent redistribution of anthracyclines into a nonnuclear vesicular compartment.

[Antitumor effect of SN-38, active form of CPT-11, on human colorectal cancer cell line].

The in vitro sensitivity testing for four human colorectal cancer cell lines to seven chemotherapeutic drugs including CPT-11, derivative of camptothecin, and its active form SN-38 were determined. MTT assay revealed that SN-38 was the most active for all four cell lines tested and its IC50's were very close to its clinically achievable plasma concentration. Relationship between exposure time and cytocidal effect of SN-38 was also investigated using MTT assay, topoisomerase-I (Topo-I) immunoblot analysis and DNA relaxation-assay, showing that IC50 value, Topo-I protein and Topo-I activity were decreased soon after the administration of SN-38 and reached to the plateau level at 24 hours. We conclude that SN-38 is very potent for colorectal cancer and the optimal schedule of CPT-11 can be the more continuous form of administration capable of as long as 24 hours exposure of its active metabolite, SN-38.

[Myocardial hemorrhage due to high-dose cyclophosphamide treatment in a case of non-Hodgkin's lymphoma].

43-year-old male with non-Hodgkin's lymphoma which was resistant to standard treatment received high-dose chemotherapy followed by autologous stem cell transplantation. He had a past history of nephrectomy due to renal cell carcinoma. He had received adriamycin at a total dose of 280mg/m2, but had no episode of heart disease. His chest radiograph, electrocardiogram and serum creatinine were within normal ranges at the start of high-dose chemotherapy. He was given 120 mg/kg of cyclophosphamide (CPM) over two days. Serum creatinine levels elevated two days before transplantation, and he felt discomfort of the chest followed by severe arrhythmia. He died of heart failure one day after the transplantation. Postmortem examination revealed diffuse myocardial hemorrhage with degeneration and necrosis of the heart muscle. CPM is one of the useful antitumor alkylating agents for the treatment of malignant neoplasms. Although conventional doses of CPM can be used without adverse cardiac effects, high-dose CPM has been reported to induce cardiotoxicity in a few cases. Patients often develop fatal acute heart failure. For the safe use of high-dose CPM, we must consider about the dosing schedule, early detection of adverse cardiac effects, and patient risk factors.

[Combination chemotherapy of advanced Hodgkin's disease with vincristine, cyclophosphamide, procarbazine, and prednisolone].

Thirty-three patients with advanced Hodgkin's disease were treated with a combination chemotherapy consisting of vincristine 1 mg/m2 iv on day 1, 8, cyclophosphamide 500 mg/m2 iv on day 1, procarbazine 100 mg/m2 p.o. day 1-7, and prednisolone 40 mg/m2 p.o. day 1-7. Twenty patients received this regimen every 4 weeks (VCPP II regimen). Furthermore, we conducted higher dose intensive VCPP II-2 regimen which was repeated every two weeks for thirteen patients. Complete response rate of both regimens was 63% (VCPP II 45%, VCPP II-2 85%). The median duration of CR was 37 + months. Leukopenia, neurotoxicity and gastrointestinal toxicity were commonly observed but were clinically manageable. These results indicate that high dose intensive chemotherapy is effective for achieving high CR rate for advanced Hodgkin's disease.

Evaluation of prognostic factors for 233 patients with recurrent advanced breast cancer.

We analyzed possible prognostic factors in 233 patients with recurrent advanced breast cancer treated primarily by adriamycin, cyclophosphamide and ftorafur (ACF) therapy and ACF modifications. The patients were in the Cancer Institute Hospital from 1977 to 1986, and were followed-up until 1989. In terms of chemotherapeutic response, complete and partial responses were observed in 31 (13%) and 100 (43%) patients, respectively. The overall median survival from the beginning of chemotherapy was 20.3 months. The factors evaluated were response to chemotherapy, performance status (PS), age, disease-free interval (DFI), menopausal status, number of metastatic sites (step classification), presence or absence of liver metastasis, presence or absence of malignant effusion, and presence or absence of prior radiotherapy. Out of the nine factors, response to chemotherapy, PS, age, DFI and liver metastasis were significant factors affecting survival in univariate analysis, and multivariate analysis of these five factors revealed the survival to be markedly affected by response to chemotherapy (P less than 0.00001), PS (P = 0.00001) and DFI (P less than 0.00001).

[Phase I-II study of hepatic intraarterial one-shot administration of adriamycin in patients with metastatic liver cancer].

For the purpose of obtaining the optimal dose of adriamycin (ADM) in hepatic intraarterial one-shot administration, phase I-II study was conducted in 14 patients with various liver cancers. The starting dose of ADM was 20 mg/m2 (4 patients) and the doses were escalated to 40 mg/m2 (5 patients), 60 mg/m2 (4 patients) and 80 mg/m2 (3 patients). One patient with salivary gland cancer showed PR for the liver metastasis. Major toxicity was leukopenia. With a dose of 40 mg/m2, 3 out of 4 patients showed nadir of WBC counts below 4,000/mm3 (2,400, 2,900, 3,100), 60 mg/m2 (1,100, 1,500, 2,200 and 2,700), and 80 mg/m2 (900, 1,200, and 1,400). Nadirs of WBC counts were observed from 9 to 15 days after the one-shot administration, and recovered above 4,000/mm3 in 1 to 3 weeks. Plasma concentrations of ADM from the peripheral vein were determined by HPLC in 12 patients, 14 courses. The curves of ADM plasma levels after 20 and 40 mg/m2 bolus injections were almost the same, and in patients treated with 60 and 80 mg/m2 the curves were also quite similar, but higher in the plasma levels, comparing with in patients with 20 and 40 mg/m2. There might be a limit of ADM tissue absorption, and above the doses 60 mg/m2, ADM might be overflowed, followed by side effects, especially leukopenia. Upon these data of venous plasma concentrations of ADM and leukopenia, the optimal dose of ADM in the hepatic intraarterial one-shot administration seemed to be 40 mg/m2.

[High-dose cyclophosphamide, thio-TEPA, etoposide with autologous bone marrow transplantation for refractory cancers].

We studied high-dose chemotherapy with autologous bone marrow transplantation (ABMT) for 10 patients with malignant lymphoma or breast cancer refractory to conventional chemotherapy. Conditioning regimen was consisted of cyclophosphamide 60 mg/kg/day, thio-TEPA 6 mg/kg/day, Etoposide 500 or 600 mg/m2/day for 3 consecutive days. Of 9 patients with measurable lesions, there were 5 with complete responses (CR) and 4 with partial responses (PR). Severe bone marrow suppression, mucositis, and diarrhea were observed in all patients. Furthermore, biliary stasis, which was unpredictable side effect, was observed in most patients. So, mucositis and/or hepatotoxicity were thought to be the dose-limiting factors. But these were not life-threatening and clinically manageable. All patients were received recombinant human granulocyte colony stimulating factor (rhG-CSF) at a dose of 300 micrograms/m2/day and which was effective for shortening the duration of leukopenia. In vitro Colony Forming Unit-granulocyte macrophage assay (CFU-GM assay) showed a significant correlation between the ability of colony formation and the days to recovery of granulocytes.

[Combination chemotherapy of ifosfamide, cisplatin and vindesine for non-small cell lung cancer].

Twenty patients with advanced non-small cell lung cancer were treated with a combination chemotherapy consisting of ifosfamide (IFX), cisplatin (CDDP) and vindesine (VDS). The treatment schedule was IFX 1.3 g/m2 i.v., on days 1-5, CDDP 20 mg/m2 i.v., on days 1-5, and VDS 3 mg/m2 i.v., on days 1 & 8, and, in principle, the regimen was repeated every 4 weeks. Of 19 evaluable patients, there were 1 CR, 7 PR, 10 NC and 1 PD, with an overall response rate of 42.1%. The median duration of responses was 7.45 months, and the median survival time of all patients was 13.2 months. The major toxicities occurring were hematologic toxicity, alopecia, gastrointestinal toxicity and peripheral neuropathy. Hematologic toxicity was severe and was judged to be dose limiting, but clinically manageable. These results indicate that this combination chemotherapy is active against non-small cell lung cancer and deserves further studies.

[Treatment of cancer in the elderly--cancer chemotherapy].

A retrospective analysis was made of elderly cancer patients (pts) who were treated with cancer chemotherapy in our Department of the Cancer Inst. Hosp. There were 180 pts above age 70 years at the start of chemotherapy between July of 1974 and December of 1988. Characteristics of these 180 pts were as follows: (1) 73 years of age in median (70-89 years), (2) 67 pts with malignant lymphoma (37%); 40 with lung ca. (22%), 20 with breast ca. (11%), stomach ca., colorectal ca., multiple myeloma and other; (3) Combination chemotherapy given to 174 pts; (4) OUTCOME: 41 pts (23%) were alive as September of 1989, and autopsy performed in 66 out of 87 pts who died in the hospital (76%). There were no special chemotherapeutic regimens only for elderly pts. Intensity of adequate chemotherapy based on therapeutic protocols was evaluated, dividing pts into two groups: full-dose group and reduced-dose group. Most pts (96%) with small cell lung cancer (SCL) were treated on protocols. For example, 12 elderly pts with SCL were treated with VEC regimen (VCR.VP-16.CTX); eight pts with full-dose and four reduced-dose, and their response rate (CR/PR) of 50%/38% and 25%/75%, respectively, and in 23 younger pts; 20 full-dose and three reduced-dose, and response rate 35%/35% and 33%/33%, respectively. There were 40 pts with acute non-lymphocytic leukemia over 60 years old, treated at Jikei University and in our Department. CR rates of these pts according to age showed a lower percentage with advancing age. Elderly pts with malignancies responsive to chemotherapy should be treated with the same regimen used in younger pts. But doses of each drug have to be adjusted to organ functions of each pt. patients with unresponsive malignancies, must be enrolled in clinical trials, and their responses and toxicities evaluated by age-stratified analysis.

[Phase I and pharmacokinetic study of KRN8602, a new morpholino anthracycline].

Phase I clinical trial of a new semi-synthetic morpholino anthracycline derivative, KRN8602, was performed. Sixteen patients with advanced malignant neoplasms refractory to standard chemotherapies received 27 courses at doses ranging from 1.5 mg/m2/day to 18 mg/m2/day by bolus injection for three consecutive days. The dose limiting toxicity was leukopenia, and a maximally tolerated dose was 18 mg/m2/day (day 1-3). The recommended dose and schedule for a phase II study is determined to be 12 mg/m2/day for three consecutive days at 3-4 weeks intervals. Among non-hematologic toxicities, nausea and vomiting were severe, but stomatitis and alopecia were rarely observed. Clinical signs of cardiotoxicity were not seen.

[Effect of recombinant human granulocyte colony stimulating factor (rhG-CSF) in patients receiving chemotherapy--phase I study].

Seventeen patients with advanced malignancy were treated with recombinant human granulocyte colony stimulating factor rhG-CSF (KRN 8601) infused intravenously over a period of 30 minutes once daily at the dose level/25 micrograms, 50 micrograms, 100 micrograms, 200 micrograms, 400 micrograms, 800 micrograms/m2 for 14 consecutive days, and the effect was compared to the period without rhG-CSF treatment. The maximum numbers of peripheral leukocyte (granulocyte) showed a dose-related increase and the nadir of leukocyte counts escalated with shortening of the period. After stopping infusion, the neutrophil count dropped to the base line level within two or three days. RhG-CSF did not affect other components of peripheral blood such as monocyte, lymphocyte, eosinophil, and hemoglobin value and platelet counts. Transient bone pain occurred in two patients receiving a dose of 800 micrograms/m2. The biochemical changes detected were increased total alkaline phosphatase activity in serum, which appeared in parallel with the increase of neutrophil numbers, and less elevation of total uric acid values. We conclude that an optimal dose of rhG-CSF is 100 micrograms/m2 (average maximum peripheral granulocyte count, 10799/microliters; nadir granulocyte count, 3772/microliters; period of neutropenia, 2.6 days), and rhG-CSF is useful for acceleration of neutrophil recovery and prevention of infection from chemotherapy.