Phase I study of sequential administration of topotecan and 5-fluorouracil in patients with advanced malignancies

Topotecan is a topoisomerase-I inhibitor, a drug that stabilizes a covalent complex of enzymes and causes strand cleavage of DNA. 5-Fluorouracil (5FU) is an antimetabolite that interferes with DNA synthesis. Preclinical studies using human cancer cell line models have shown potential therapeutic synergy between these two drugs by showing the maximum cytolytic effect using sequential 5FU followed by topotecan. In the current study, 5FU was used at a fixed dose of 375 mg/m2 given intravenously for five consecutive days on a 28 day cycle. Topotecan was dose-escalated in cohorts of patients from 0.5 to 1.0 mg/m2 given intravenously for 5 days after the 5FU dose. Eleven patients were entered at different dose levels. Both hematological and gastrointestinal toxicity were dose limiting. Diarrhea was the dose-limiting toxicity at the dose of 0.75 mg/m2 of topotecan. Two cases of grade 4 neutropenia were also observed at this dose level. One patient with small cell lung cancer had a complete response, while one patient with metastatic colorectal cancer had a partial remission. Three other patients had stable disease, lasting between 6 and 8 months. Overall, the regimen was well tolerated. A phase II study using a dose of 5FU at 375 mg/m2 followed by topotecan at 0.75 mg/m2 intravenously over 5 days every 28 days is recommended.     

Phase I Study of Sequential Administration of Topotecan and 5-Fluorouracil in Patients with Advanced Malignancies

Topotecan is a topoisomerase-I inhibitor, a drug that stabilizes a covalent complex of enzymes and causes strand cleavage of DNA. 5-Fluorouracil (5FU) is an antimetabolite that interferes with DNA synthesis. Preclinical studies using human cancer cell line models have shown potential therapeutic synergy between these two drugs by showing the maximum cytolytic effect using sequential 5FU followed by topotecan. In the current study, 5FU was used at a fixed dose of 375 mg/m² given intravenously for five consecutive days on a 28 day cycle. Topotecan was dose-escalated in cohorts of patients from 0.5 to 1.0 mg/m² given intravenously for 5 days after the 5FU dose. Eleven patients were entered at different dose levels. Both hematological and gastrointestinal toxicity were dose limiting. Diarrhea was the dose-limiting toxicity at the dose of 0.75 mg/m² of topotecan. Two cases of grade 4 neutropenia were also observed at this dose level. One patient with small cell lung cancer had a complete response, while one patient with metastatic colorectal cancer had a partial remission. Three other patients had stable disease, lasting between 6 and 8 months. Overall, the regimen was well tolerated. A phase II study using a dose of 5FU at 375 mg/m² followed by topotecan at 0.75 mg/m² intravenously over 5 days every 28 days is recommended.     

In vitro and in vivo activity of antifungal agents in combination with fleroxacin, a new quinolone

The in vitro and in vivo interaction of fleroxacin with amphotericin B (Amph B), flucytosine (5-FC) and azoles against Candida albicans strains was tested. In vitro the interaction between fleroxacin and various antifungals was not dependent on the incubation time. Fleroxacin neither enhances nor antagonizes the in vitro activity of Amph B at high concentration (50-100 micrograms/ml). Fleroxacin has a synergistic effect with ketoconazole (KETO), but this is not observed with itraconazole (ITRA) or fluconazole (FLU). In no instance antagonism was observed. The activity of 5-FC was antagonized by fleroxacin being generally reduced by 2-4 dilution steps. In murine candidosis the efficacies of all antifungal drugs were not influenced by addition of 100 mg/kg fleroxacin. Therefore, the effects seen in in vitro tests are most probably not relevant for the clinical use of a combination of fleroxacin with antifungal drugs.     

A Phase II Trial of Deferoxamine in Patients with Hormone-Refractory Metastatic Prostate Cancer

The management of hormone-refractory metastatic prostate cancer remains a therapeutic dilemma. We report the results of a phase II trial with deferoxamine administered at a dose of 50 mg/kg (maximum dose 5 g) administered intravenously over 8 hr daily, repeated for 5 days at 4-week intervals for 2 courses. Fourteen patients with advanced hormone-refractory prostate cancer were treated and 28 courses were delivered. Essentially no toxicity was observed. Using combined clinical and prostate-specific antigen (PSA) criteria, 13 of 14 patients had disease progression. However, 9 of 14 patients had stable measurable or evaluable disease and progressed solely based on PSA criteria. Deferoxamine in this dose and schedule has no activity in hormone-refractory prostate cancer. Further investigation of the effect of deferoxamine on PSA production/expression is warranted.     

Schedule-dependent variations in the response of murine P388 leukemia to cyclophosphamide in combination with interferons-alpha/beta

Positive therapeutic effects of interferons (IFNs) in combination with other therapies will depend on defining modalities, doses, and timing of treatment in the setting of varied tumor burdens. When 10(4) P388 leukemia cells were inoculated i.p. on day 0 in BALB/c x DBA/2 F1 mice, all mice died within 18 days if left untreated. Murine IFN-alpha/beta (5 x 10(5) units) injected daily i.p. on days 5-9 resulted in 20% increase in life span (ILS) (P less than 0.0001). Cyclophosphamide (CY) (100, 33, or 15 mg/kg) was injected i.p. once 2 days before start (day 3), simultaneously with start (day 5), or 2 days after cessation of IFN treatment (day 11). When 100 mg/kg CY alone were injected on day 3 or 5, all mice survived more than 90 days and were considered cured. When IFN was given after this curative dose of CY, more tumor deaths occurred; up to 100% of the mice died when 100 mg/kg CY on day 3 were combined with IFN on days 5-9. Increased mortality with the combination was not due to added toxicity of CY and IFN since the mice developed abdominal tumors and ascites. Mice not inoculated with tumor cells and treated similarly suffered only a transient weight loss, had only moderate white count depression, and did not die. When IFN was injected before CY on days 1-5 (instead of days 5-9), IFN did not alter the effectiveness of CY (100 mg/kg on day 5). In contrast to these results, when CY (100 mg/kg) was administered on day 11, after IFN (days 5-9), an augmented survival occurred with 119% ILS and 40% cures (CY alone on day 11 resulted in 69% ILS but no cures). In addition, when CY at a lower dose of 15 mg/kg was injected in combination with IFN, survival was consistently augmented by IFN; e.g., CY alone on day 3 caused 40% ILS and with IFN (days 5-9) 60% ILS (P less than 0.0001). Qualitatively similar findings were obtained when P388 leukemia cells were inoculated s.c. and the drugs delivered i.p. Inhibition by IFN of antitumor effects of a second alkylating agent, 1,3-bis(2-chloroethyl)-1-nitrosourea, was also identified. Thus, IFN-alpha/beta potentiated suboptimal CY effects for P388 leukemia, had neutral effects when injected before CY treatment, and inhibited antitumor activity of curative CY or nitrosourea schedules.     

5-Fluorouracil and isoprinosine in the treatment of advanced colorectal cancer. A limited phase I, II evaluation

We studied the effects of 5-fluorouracil (5-FU) and isoprinosine (ISO) on 15 patients with previously untreated metastatic colorectal carcinoma. The patients were treated in a limited Phase I, II protocol. All patients received a fixed ISO dose of 4 g orally on days 1 through 5 of each cycle. Each cycle was repeated every 35 days. The first seven patients were treated with an initial 5-FU dose of 7.5 mg/kg intravenously (IV) on days 1 through 5, which was escalated to 11.5 mg/kg IV after the first course and to 13 mg/kg IV after the second course. The next eight patients were treated with an initial 5-FU dose of 11.5 mg/kg IV on days 1 through 5, which was escalated to 13 mg/kg IV on days 1 through 5. No major responses (complete or partial) were documented. Median survival for all evaluable patients was 33 weeks. Toxicity was predominantly gastrointestinal and hematologic and was considered moderate. Our data suggest that 5-FU and ISO, at the doses used, were ineffectual in the treatment of metastatic colorectal carcinoma.     

Combining suramin and a chimeric toxin directed to basic fibroblast growth factor receptors increases therapeutic efficacy against human melanoma in an animal model.

BACKGROUND: Suramin, which binds to and blocks autocrine and paracrine growth factors required for the proliferation of neoplastic cells, is a clinically effective antitumor agent against some human tumors; however, efficacy often is limited by toxicity. In this study, suramin treatment was combined with a fibroblast growth factor (FGF) receptor-directed toxin chimera, basic FGF-saporin (bFGF-SAP), based on the authors' previous observations that autocrine-mediated resistance to bFGF-SAP in melanoma in vitro is abrogated by suramin treatment. METHODS: Severe-combined immunodeficient-Beige mice bearing SK-Mel-5 human melanoma xenografts received weekly treatments of suramin (200 or 75 mg/kg intraperitoneally) beginning on Day 5 after tumor implantation followed 18 hours later by a treatment with bFGF-SAP (0.5-5 microg/kg intravenously) for 4 weeks. The optimal interlude between the administration of suramin and bFGF-SAP was determined by tumor excision assays. The efficacy of combination therapy as a function of alternative dosing regimens was determined by tumor growth inhibition (TGI) studies. RESULTS: Fifty days after implantation, a 79-82% TGI was observed in animals receiving the suramin (200 mg/kg) plus bFGF-SAP combination regimens compared with median tumor volumes from vehicle-treated controls (3070+/-440 mm(3)). TGI observed for combination therapies varied significantly (P<0.05-0.001) from TGI observed in treatment groups receiving suramin alone (57%) or bFGF-SAP alone (34-38%). Combining bFGF-SAP (5 microg/kg) with a low, therapeutically ineffective dose of suramin (75 mg/kg) produced a 68% rate of TGI compared with controls, thus lowering the therapeutic effective dose of suramin and eliminating the suramin-related lethal toxicity (12% mortality rate) observed in animals treated with high dose suramin. CONCLUSIONS: The results of the current study suggest that combining suramin with receptor-directed therapies offers a more effective regimen for the treatment of malignant melanoma.     

A phase I, pharmacokinetic and biologic correlative study of oblimersen sodium (Genasense, G3139) and irinotecan in patients with metastatic colorectal cancer.

PURPOSE: To assess the feasibility and antitumor activity of oblimersen sodium, an antisense oligonucleotide directed to the Bcl-2 mRNA, combined with irinotecan in patients with advanced colorectal carcinoma, characterize the pharmacokinetic behavior of both oblimersen sodium and irinotecan, and examine Bcl-2 protein inhibition in peripheral blood mononuclear cells (PBMC). PATIENTS AND METHODS: Patients were treated with escalating doses of oblimersen sodium administered by continuous intravenous infusion (CIVI) days 1-8, and irinotecan administered intravenously on day 6 once every 3 weeks. RESULTS: Twenty patients received a total of 84 courses at doses ranging from 3 to 7 mg/kg/day for oblimersen sodium and from 280 to 350 mg/m2 for irinotecan. Febrile neutropenia and diarrhea limited escalation of oblimersen sodium and irinotecan to 5 mg/kg/day and 350 mg/m2, respectively. Other toxicities included nausea, vomiting, fever and fatigue. Steady-state plasma concentrations were achieved within 48 h of beginning oblimersen sodium treatment and the agent was undetectable 24 h after the discontinuation of the infusion. Reduction in levels of Bcl-2 protein in PBMC was documented following treatment with oblimersen sodium. One patient experienced a partial response and 10 additional patients had stable disease lasting 2.5-10 months. CONCLUSIONS: The combination is well tolerated at the recommended phase II oblimersen sodium dose of 7 mg/kg/day CIVI days 1-8 with irinotecan 280 mg/m2 intravenously on day 6 every 3 weeks.     

Treatment of patients with advanced colorectal carcinomas with fluorouracil alone, high-dose leucovorin plus fluorouracil, or sequential methotrexate, fluorouracil, and leucovorin: a randomized trial of the Northern California Oncology Group

We compared the effectiveness of fluorouracil (5-FU) alone (arm A), high-dose leucovorin plus 5-FU (arm B), and sequential methotrexate, 5-FU, and leucovorin (arm C) for treatment of patients with advanced colorectal carcinomas who had not received prior chemotherapy. Arm A consisted of infusions of 5-FU at 12 mg/kg/d intravenously (IV) for 5 days followed by weekly infusions of 5-FU at 15 mg/kg; arm B consisted of leucovorin infusions at 200 mg/m2/d IV plus infusions of 5-FU at 400 mg/m2/d IV on days 1 through 5 of a 28-day cycle; arm C consisted of methotrexate at 50 mg/m2 orally every 6 hours for five doses followed by infusions of 5-FU, 500 mg/m2 IV, and leucovorin, 10 mg/m2 orally, every 6 hours for five doses every other week. A total of 265 patients were entered into the trial, of whom 249 (94%) were fully evaluable. The objective response rate (complete [CR] plus partial [PR] responses) was 17.3% on arm A, 18.8% on arm B, and 19.8% on arm C (log-rank test, P greater than .4). The median time to failure was 138 days on arm A, 166 days on arm B, and 182 days on arm C (log-rank test, P values of arm A v B = .06; arm A v arm C = .04). Median survival was 345 days on arm A, 324 days on arm B, and 356 days on arm C (log-rank test, P greater than .4). Treatment with 5-FU alone was significantly more dose intensive and more toxic than either of the experimental combinations. The rates of grade 3 or greater nonhematologic toxicity were 42.3% on arm A, 24.3% on arm B, and 14.3% on arm C. Hematologic toxicity was milder but had the same pattern. This study indicates that these regimens of high-dose leucovorin plus 5-FU and sequential methotrexate, 5-FU, and leucovorin are not more effective than is 5-FU alone for treatment of patients with colorectal carcinomas when 5-FU is administered at high-dose intensity.     

Treatment with the novel anti-angiogenic agent PI-88 is associated with immune-mediated thrombocytopenia.

BACKGROUND: The novel molecule PI-88 is a highly sulfonated oligosaccharide which inhibits heparanase activity and competes with heparan sulfate binding of growth factors such as FGF and VEGF. Preclinical data demonstrates that PI-88 inhibits angiogenesis and has anti-metastatic effects. The aim of this phase I study was to determine the recommended dose and toxicity profile of PI-88. PATIENTS AND METHODS: PI-88 was given intravenously in increasing duration of administration (0.57 mg/kg for 2 h, 0.57 mg/kg/day for 1 day, 4, 7 and 14 consecutive days) and then increasing dose for 14 consecutive days (1.14 mg/kg/day and 2.28 mg/kg/day) in patients with advanced malignancies until dose-limiting toxicity (DLT) was observed. Fourteen assessable patients with advanced malignancies received PI-88 intravenously. RESULTS: DLT was thrombocytopenia. The thrombocytopenia appeared to be immunologically mediated with the development of anti-heparin platelet factor 4 complex antibodies. There were no other significant toxicities. At the final dose and schedule (2.28 mg/kg/day for 14 days), there was limited evidence of biological activity as measured by the surrogate marker activated partial thromboplastin time (APTT), although two patients had stabilisation of disease. CONCLUSIONS: In conclusion, PI-88 at a dose of 2.28 mg/kg/day for 14 days resulted in dose-limiting thrombocytopenia which appeared to be immune related. Limited evidence of biological activity was noted. Alternate scheduling and routes of administration are now being explored.     

Antineoplastic activity of two taxol derivatives on an ovarian tumor xenografted into nude mice

In order to compare the antineoplastic activities of taxol A, taxol B, a mixture of the two (taxol A 72%) and vinblastine, a human ovarian tumor serially transplanted into 104 female athymic mice was used. In the first experiment (11th passage), the antineoplastic activities of taxol A, taxol B and the mixture taxol AB were tested. The same dose was used in each case (12.5 mg/kg i.e. 1/20 of the evaluated LD50 value). It was administered subcutaneously for 5 consecutive days. Three courses of treatment were performed, with 2 rest periods of 1 week in between. All the taxol derivatives produced a statistically significant delay in the tumor growth. However, taxol B had the lowest chemotherapeutic response. In the second experiment (18th passage), different dose levels were administered (mixture 12.5 mg/kg/day x 4 - taxol A 8.8. mg/kg/day x 4 - taxol B 3.5 mg/kg/day x 4 - vinblastine 0.5 mg/kg/day x 2). For all the taxol derivatives 4 treatment courses with 3 rest periods of 4 days were used, and for vinblastine 4 treatment courses with 3 rest periods of 1 week. At the end of the second experiment, vinblastine, taxol A and a mixture of the two showed similar significant activity, whereas no objective antitumor response was observed following the taxol B treatment at the dose level chosen. The experimental results obtained clearly demonstrate that, in the taxane system, the greatest degree of antineoplastic activity can be attributed to taxol A.     

酒石酸长春瑞滨脂质微球注射液对荷人乳腺癌裸鼠肿瘤生长的影响

目的: 研究酒石酸长春瑞滨脂质微球注射液(NVB-lip)对荷人乳腺癌裸鼠肿瘤生长的影响。方法: 35只雌性BALB/c-nu裸鼠,随机分为NVB-lip高(10 mg/kg)、中(5 mg/kg)、低(2.5 mg/kg)剂量组,阳性对照组(酒石酸长春瑞滨注射液,5 mg/kg)和阴性对照组(脂质化空白溶液),每组7只。给裸鼠接种人乳腺癌BCAP-37瘤株,待成瘤后,每只动物每次按0.20 mL经尾静脉注射给药,间隔3~4 d注射1次,每周注射2次,共注射6次。在第1次注射后第4、7、11、14、18和23天时分别称小鼠体质量和测量肿瘤体积,计算得出相对肿瘤体积、相对肿瘤增殖率和肿瘤抑制率。结果: 与阴性对照组相比,各组荷瘤裸鼠体质量差异均无统计学意义(P均>0.05)。NVB-lip各剂量组的相对肿瘤体积和相对肿瘤增殖率显著减小,肿瘤抑制率显著增大,差异均有统计学意义(P<0.01)。结论: NVB-lip在2.5~10 mg/kg范围内抑瘤作用明显,具有可开发潜力。     

Phase I study of rubitecan and gemcitabine in patients with advanced malignancies.

BACKGROUND: Rubitecan (9-nitrocamptothecin, 9-NC, Orathecin) and gemcitabine have single-agent activity in pancreatic and ovarian carcinoma. We conducted a phase I trial to evaluate the maximum tolerated dose (MTD) and toxicities of this combination in advanced malignancies. PATIENTS AND METHODS: Twenty-one patients with refractory or recurrent malignancies were enrolled in this dose escalation trial. Dose escalation proceeded from a starting level of rubitecan at 0.75 mg/m(2)/day administered orally on days 1-5 and 8-12 in combination with gemcitabine 1000 mg/m(2) administered intravenously on days 1 and 8 of a 21-day cycle. RESULTS: The MTD was defined as rubitecan 1 mg/m(2) administered orally days 1-5 and 8-12, and gemcitabine 1000 mg/m(2) administered intravenously over 30 min days 1 and 8, given every 21 days. Dose-limiting toxicity was myelosuppression including neutropenia and thrombocytopenia. Other side effects included diarrhea, nausea, vomiting and fatigue. Five patients with stable disease were observed among 18 evaluable patients. CONCLUSIONS: The recommended phase II dose is rubitecan 1 mg/m(2) given orally on days 1-5 and 8-12 in combination with gemcitabine 1000 mg/m(2) as a 30-min intravenous infusion on days 1 and 8 of a 21-day cycle.     

Patterns of cytomegalovirus retinitis in immunocompromised patients treated with 9-(2-hydroxy-1-(hydroxymethyl)ethoxymethyl) guanine (ganciclovir).

Five immunocompromised patients, four with AIDS and one who had undergone bone marrow transplantation, showing ocular signs of cytomegalovirus retinitis, were treated with 9-(2-hydroxy-1-(hydroxymethyl)ethoxymethyl) guanine (Ganciclovir), given intravenously at the dose of 5 mg/kg twice daily for a period ranging from 10 to 20 days. At the end of the treatment, in 4 of 5 patients, the ophthalmoscopic picture had improved, with reduced exudation and an arrest in the progression of retinal necrosis, the pattern clearly indicating a trend towards organization and scarring. Complete resolution of the retinitis without subsequent relapse was observed only in the bone marrow transplant patient, who recovered immunologically, whereas improvement of the eye involvement was only transient in the three AIDS patients.     

OSI-211, a novel liposomal topoisomerase I inhibitor,is active in SCID mouse models of human AML and ALL

OSI-211 (liposomal lurtotecan), was evaluated using several different dose schedules (1mg/kg, d1-5, 1.75 mg/kg d1, 3, 5 and 6 mg/kg d1, 8) in severe combined immunodeficient (SCID) mouse models of acute myelogenous leukemia (AML) and acute lymphocytic leukemia (ALL) with early treatment (ET, days 6-8) or late treatment (LT, days 15-19), examining early and advanced disease, respectively. Due to the aggressive nature of the Molt-4 model, the ET and LT were accelerated to day 3 or 4 and day 8 post-implant, respectively. For each model, 2 x 10(7) (KBM-3B) or 1 x 10(7) (Molt-4, HL-60 and CEM) leukemia cells were injected intravenously into the tail vein. Each control and test group consisted of eight animals. All three schedules (1mg/kg qd1-5, 1.75 mg/kg d1, 3, 5 and 6 mg/kg d1, 8) increased the life span of OSI-211 treated animals in each model, with a tendency toward improved efficacy with the 6 mg/kg d1, 8 schedule. As a result, the activity of the 6 mg/kg d1, 8 schedule is detailed for each model. ET significantly (P<0.005) increased survival in the KBM-3B model with 86% long-term survivors (LTS). Using PRC analysis, human beta-globin gene sequences in one or several tissues were amplified in all but 3 LTS, suggesting minimal residual disease in 26 of the 29 LTS. LT also significantly (P<0.005) improved average life span in the KBM-3B model, with an average ILS=196+/-11% and one LTS. Treatment of HL-60 leukemia animals significantly (P<0.005) increased life span, with an ILS=213+/-9% and two LTS for ET, and with an ILS=219+/-4% and no LTS for LT. Treatment of Molt-4 animals, the most aggressive leukemia model tested, significantly (P<0.005) increased life span, with an average ILS=181+/-3% and no LTS for ET and an average ILS=172+/-1% with no LTS for LT. In the CEM model, ET resulted in a significantly (P<0.005) improved ILS=244+/-24% with one LTS. In comparison to OSI-211, treatment with DaunoXome, the liposomal formulation of daunorubicin, a drug with clinical efficacy in AML and ALL, had no effect on survival in the KBM-3B, nor Molt-4 A4 leukemia models when administered at its maximum or near maximum tolerated doses of 3mg/kg d1, 8. These data demonstrate that OSI-211 has potent antileukemia activity in preclinical SCID mouse AML and ALL leukemia models, supporting the clinical investigation of OSI-211 for hematological malignancies.     

Minimally-invasive debulking of ovarian cancer in the rat pelvis by means of photodynamic therapy using the pegylated photosensitizer PEG-m-THPC

Interstitial photodynamic therapy (PDT) using the pegylated photosensitizer PEG-m-THPC was evaluated as a minimally-invasive procedure to selectively debulk unrespectable pelvic ovarian cancer (NuTu-19) in immunocompetent rats. To assess tumour selectivity, PEG-m-THPC at dosages of 0.3, 3.0 and 30 mg kg(-1) body weight was administered intravenously to 30 rats 4 weeks following tumour induction. Eight days later laser light at 652 nm and optical doses ranging from 100 to 900 J cm(-1) diffuser-length was delivered by an interstitial cylindrical diffusing fibre inserted blindly into the pelvis. Three days following light application, the volume of necrosis was measured and the damage to pelvic organs was assessed histologically on cross sections. For analysis of survival, 20 tumour-bearing rats received PDT using drug doses of 3 or 9 mg kg(-1) body weight and an optical dose of 900 J cm(-1) diffuser-length, whereas ten untreated tumour-bearing rats served as controls. The histological assessment of PDT induced necrosis showed a non-linear dose-response for both the photosensitizer dose and the optical dose. The lowest drug dose activated with the highest optical dose did not induce more necrosis than seen in tumour-bearing control animals. The same optical dose induced necrosis of 17 mm in diameter using 30 mg kg(-1) and 11 mm using 3 mg kg(-1) photosensitizer. The optical threshold for induction of significant necrosis was between 100 and 300 J cm(-1) diffuser-length for 30 mg kg(-1) and between 300 and 500 J cm(-1) for 3 mg kg(-1) PEG-m-THPC. Significant damage to normal pelvic organs was only seen if 30 mg kg(-1) photosensitizer was activated with optical doses of 700 J cm(-1) or more. In the survival study, all treated animals survived PDT for at least 2 weeks and the intestinal and urinary tract remained functional. No clinical signs of blood vessel or nerve injury were observed. Mean overall survival of untreated tumour-bearing rats was 25.0 +/- 4.5 days compared to 38.4 +/- 3.8 days and 40.0 +/- 3.6 days for rats treated with 3 mg kg(-1) or 9 mg kg(-1) PEG-m-THPC mediated PDT respectively (P < 0.05). We conclude that PEG-m-THPC mediated PDT has a favourable therapeutic window and that this minimally-invasive procedure can reduce pelvic cancer bulks effectively and selectively.     

紫杉醇联合卡铂与氟尿嘧啶联合卡铂治疗艾滋病并发晚期阴茎癌的临床对比分析

目的比较紫杉醇联合卡铂与5-氟尿嘧啶（5-Fu）联合卡铂治疗艾滋病并发晚期阴茎癌患者临床疗效、不良反应及预后。方法选择经病理或细胞学以及血清学证实的58例艾滋病并发晚期阴茎癌患者,其中30例接受紫杉醇联合卡铂方案化疗（TC组）,28例接受5-Fu联合卡铂方案化疗（FC组）,按实体瘤的疗效评价标准(RECIST)1.0版评价近期疗效,按美国癌症研究所常见毒性判定标准（NCI-CTC）3.0版评价不良反应。结果58例均可评估疗效,TC组和FC组的客观总有效率分别为56.7%和17.9%（χ²=9.265,P=0.002）,中位疾病进展时间分别为11.15月和7.22月（χ²=6.737,P=0.009）,中位生存时间分别为17.36月和9.11月（χ²=10.646,P=0.001）。两组主要不良反应均为骨髓抑制及恶心呕吐,Ⅲ～Ⅳ度白细胞减少发生率分别为46.4%和40.0%（χ²=0.222,P=0.637）,Ⅲ～Ⅳ度恶心呕吐的发生率分别为36.0%和34.78%（χ²=0.008,P=0.930）。结论紫杉醇联合卡铂化疗方案治疗艾滋病并发晚期阴茎癌是安全和有效的。     

Ondansetron (GR 38032F): a novel antiemetic effective in patients receiving a multiple-day regimen of cisplatin chemotherapy.

In a multicenter trial, we evaluated the antiemetic efficacy of ondansetron, a selective serotonin type 3 (5-HT3) receptor antagonist, in 42 adult chemotherapy-na?ve patients receiving a multiple-day cisplatin regimen (20-40 mg/m2 per day for 4-5 days). Thirty-one patients received 3 daily doses of ondansetron (0.15 mg/kg) given intravenously every 6 hours (first dose 30 minutes prior to cisplatin administration); 11 additional patients received an identical dosage and schedule except that a fourth daily dose was added 17.5 hours after cisplatin administration. No other antiemetics were administered. Forty patients were evaluable for efficacy response. Thirteen patients (33%) had no vomiting at any time during the 5-day study. When emetic episodes were evaluated on a daily basis, complete protection (zero emetic episodes) ranged from 50-75%, and major protection (less than or equal to 2 emetic episodes) ranged from 65-93%. The majority of therapy failures occurred on days 3 and 4. Side effects were minor and transient; no extrapyramidal side effects were observed. Ondansetron appears to be a safe and effective antiemetic when administered during a multiple-day cisplatin-containing chemotherapy regimen.     

Reduction of cisplatin toxicity by fosfomycin in animal models

The protective effect of fosfomycin against cisplatin-induced toxicities was studied in rats. A total of 64 Fischer rats were injected intravenously with daily doses of 1, 2, 5 and 10 mg/kg of cisplatin with or without 300 mg/kg of fosfomycin for a period varying from 1 to 10 days. The same total dose of 10 mg/kg of cisplatin was given to all animals. Cisplatin-induced toxic side-effects of body weight loss, nephrotoxicity and ototoxicity were significantly reduced functionally or histopathologically by the combined administration of cisplatin and fosfomycin. A comparison of different dosage schedules with a total dose of 10 mg/kg of cisplatin showed that a higher daily dose for a shorter time period produced more marked toxicities.     

Intrathecal ACNU for the treatment of a meningeal gliomatosis model

A nitrosourea derivative, ACNU (nimustine hydrochloride), is often used in the chemotherapy of brain tumors and shows considerable efficacy, since it crosses the blood-brain barrier (B.B.B.). This drug is also considered to be useful for intrathecal treatment of meningeal gliomatosis (MG) because of its short half-life in the blood or cerebrospinal fluid (CSF) and its strong cytotoxicity for glioma cells. In order to evaluate the efficacy of intrathecal therapy of MG with ACNU, MG models, which were produced by intracisternal inoculation of rat C6 glioma, were treated with intrathecal or intravenous administration of ACNU. When intrathecally administered 1 day or 3 days after tumor inoculation, ACNU (1 mg/kg) significantly prolonged the survival time of MG rats, where ILS was 35.7 to 42.9% and 24.1 to 25.0%, respectively. In MG rats which were treated intrathecally with ACNU (1 mg/kg) 5 days after tumor inoculation or intravenously with ACNU (15 mg/kg), ACNU failed to prolong survival time compared with the controls. It might therefore be suggested that intrathecal chemotherapy with a low dose of ACNU is effective in the early stages of MG, in which intravenous treatment with a high dose of ACNU is ineffective.