Combined use of gemcitabine and radiation in mice.

The aim of this study was to explore, in a murine tumor, if the effectiveness of radiation, in doses and schedules commonly used in clinical practice is potentiated by the combined use of the recently developed drug gemcitabine. Gemcitabine (30-360 mg/kg b.w.) was administered i.p. in female C3D2F1 mice bearing a mammary adenocarcinoma alone or combined with X-rays. Firstly, gemcitabine (single administration) was administered alone or at 20 min, 4 h, and 24 h before X-ray treatments. The significant effect observed only at 24 h time interval, depended on the X-ray dose and not on the gemcitabine dose. Secondly, 4 gemcitabine administrations every 3 days were used in fractionated combined schedules (overall treatment time of 10 days). We studied the relationship among different doses of gemcitabine, alone or combined with 10 daily X-ray treatments (2 Gy/fraction). We observed an interactive effect of gemcitabine up to its threshold dose of 60 mg/kg/fraction. Furthermore, 10 X-ray daily treatments and 4 X-ray treatments every 3 days (total doses 20-40 Gy) were performed with gemcitabine 60 mg/kg/fraction to study the effect of different doses and schedules of X-rays. Tumor growth delays increase with higher X-ray doses, and this occurs more with 4 X-ray treatments than with 10 X-ray treatments. Our results re-affirm the uselessness of high gemcitabine doses, and indicate the effectiveness of combined gemcitabine-radiation fractionated protocols.

Schedule dependent toxicity and efficacy of combined gemcitabine/paclitaxel treatment in mouse adenocarcinoma.

Increased interest in combining drugs with different targets has emerged over recent years. Our study aims at evaluating the effectiveness of combined gemcitabine/paclitaxel treatment taking into consideration doses, schedules, and toxicity. A spontaneous mammary carcinoma was transplanted into the right-hind foot of C3D2F1 mice. Paclitaxel (in doses from 20 to 80 mg/kg b.w.) and gemcitabine (in doses from 30 to 480 mg/kg b.w.) were administered i.p. in single or fractionated treatments. Toxicity and tumor growth delay (TGD) were the endpoints. TGDs for different gemcitabine doses in single administration (120, 240, and 360 mg/kg) overlapped (TGD approximately = 2.5 days). Toxicity was very high in daily administration. Results with gemcitabine alone showed the efficacy of treatments every 3 days. TGDs in fractionated treatments of 60 and 120 mg/kg x 4 were of approximately equals 16 days. Also in this case, tumor growth curves overlapped pointing out the uselessness of the high drug doses. For combined treatments, we used only fractionated protocols, administering gemcitabine every 3 days. Paclitaxel was administered alone in one or two fractions and with different sequences in respect to gemcitabine administration. With 120 mg/kg of gemcitabine all the protocols showed an increased unacceptable toxicity. The best result was obtained administering paclitaxel 40 mg/kg on days 1 and 15 and gemcitabine 60 mg/kg on days 3, 6, 9, and 12 (TGD = 38.2 days). The light toxicity and the high efficacy obtained with this protocol indicate the possible use of gemcitabine/paclitaxel treatment in clinical practice.

Hyperthermia and paclitaxel--epirubicin chemotherapy: enhanced cytotoxic effect in a murine mammary adenocarcinoma.

Multimodality therapy is considered of great interest in the treatment of locally advanced solid tumours. In previous experiments, paclitaxel (TX) and epirubicin (EP) were combined with different schedules, obtaining a superadditive effect on the growth of a murine mammary carcinoma. In the present study, the authors have analysed the possible use of hyperthermia (HT) to increase the efficacy of TX and EP combinations. Tumours were transplanted into the right hind foot of female hybrid (C3D2F1) mice. Both TX and EP were administered i.p in two different doses. Hyperthermia was applied using a water bath at 43.2 degrees C for 1 h. Results were analysed in terms of Tumour Growth Delay (TGD). The maximum tolerated doses in combined protocols were TX 45 mg/kg and EP 9 mg/kg, with an interval time of 24h between the two administrations. TGDs of some of the schedules performed are reported: EP + HT = 11 days, TX + HT = 16 days, TX + EP (with an interval time of 24 h) = 14 days, and TX + EP + HT = 22 days. In the experimental model, HT significantly increases the effects of both TX and EP. TX + EP + HT treatment is the most effective (significantly different from TX + EP), but not in a significant way when compared to TX + HT treatment. These results suggest the possible use of a TX + HT protocol for local tumour response, whereas EP could be added in order to achieve a better systemic control.

Hyperthermia enhances the response of paclitaxel and radiation in a mouse adenocarcinoma.

PURPOSE: The aim of our study was to investigate if the efficacy of paclitaxel and paclitaxel-radiation treatments in vivo could be enhanced by hyperthermia. MATERIALS AND METHODS: Paclitaxel was administered i.p. in doses from 30 to 60 mg/kg b.w. to (C3D2F1) mice bearing spontaneous mammary carcinoma. Local hyperthermia (41 degrees, 42 degrees, 43 degrees C) was carried out by immersing tumor-bearing legs in a water bath for 1 h. Single X-ray treatments from 10 to 90 Gy were performed. Tumor growth delay (TGD) or tumor control dose (TCD(50), radiation dose needed to induce local tumor control in 50% of irradiated animals) were the endpoints. RESULTS: A significant increase of dose-dependent growth delay was observed in paclitaxel and 43 degrees C hyperthermia combined treatments, and a superadditive effect was seen with paclitaxel 45 mg/kg. Combined treatments with hyperthermia at 41 degrees and 42 degrees C were less effective. Administration of paclitaxel 24 h, 4 h, and 15 min before or 15 min and 4 h after hyperthermic treatments produced similar results (TGDs varying from 22.1 to 17 days), and administering paclitaxel 48 h before or 24 h after hyperthermic treatments decreased TGDs (about 10 days). Trimodality treatment (paclitaxel 45 mg/kg, hyperthermia, and X-ray), with a TCD(50) of 14. 1 Gy, in respect to the TCD(50) of 53.1 obtained with X-ray alone, was the most effective. CONCLUSIONS: Hyperthermia enhanced the effectiveness of paclitaxel in all the tested protocols. Our results show a superadditive effect of paclitaxel 45 mg/kg combined with a hyperthermic treatment of 1 h at 43 degrees C. Trimodality treatment, evaluated in terms of percentage of cures, shows a very high enhancement ratio.

Greater antitumor efficacy of paclitaxel administered before epirubicin in a mouse mammary carcinoma.

Combined treatment with paclitaxel and anthracyclines is increasingly being tested in clinical practice. Epirubicin is in general administered before paclitaxel. We have investigated, using a murine mammary adenocarcinoma, whether the efficacy and toxicity of this combination is influenced by treatment sequence, different time intervals and dose intensity. The tumor was transplanted into the right hind foot of C3D2F1 female mice. Paclitaxel was administered i.p. in doses ranging from 15 mg/kg to 75 mg/kg and epirubicin (i.p. or i.v.) in doses from 9 mg/kg to 30 mg/kg. The hepatic and peritoneal toxicity observed with epirubicin administration increased in combined treatments (stronger with i.p. than i.v. epirubicin administrations) and was dose-dependent. When paclitaxel and epirubicin were administered simultaneously or paclitaxel was given 24 h before epirubicin, the same tumor growth delays were obtained in all groups. A smaller effect was observed when paclitaxel was administered 24 h after epirubicin. Increasing the epirubicin or paclitaxel dose led to higher tumor growth delays but also an increased toxicity. In conclusion, in this experimental model, the administration of 45 mg/kg paclitaxel before 15 mg/kg epirubicin was very effective and the increased toxicity can be limited by introducing an interval of 24 h between drug administrations. These results should be considered when designing clinical trials.

Enhancement of radiation response by paclitaxel in mice according to different treatment schedules.

PURPOSE: The aim of our study was to determine if paclitaxel could be used as a radiosensitizer in vivo. MATERIALS AND METHODS: Paclitaxel was tested as a single agent and combined with an X-ray treatment. Paclitaxel was administered i.p. in doses from 30 to 120 mg/kg b.w. to (C3D2F1) mice bearing spontaneous mammary carcinoma. Tumor growth delay (TGD) or tumor control dose (TCD50, radiation dose needed to induce local tumor control in 50% of irradiated animals) and moist desquamation dose (MDD50, radiation dose needed to induce serious moist desquamation in 50% of the non-tumor-bearing feet) were the endpoints. DNA flow cytometric analysis was performed. RESULTS: DNA analysis demonstrated a G2/M block of tumor cells and a depletion of cells in S phase, with a maximum at 24 h from paclitaxel administration. Administering paclitaxel, in graded doses, 15 min before a 10-Gy X-ray treatment resulted in a linear regression line, almost parallel to that with paclitaxel alone, with a growth delay of about 6 days. In contrast, varying the X-ray dose with a constant paclitaxel injection (45 mg/kg b.w.) treatment showed some degree of synergism as the linear regression curves diverged. Interval time and sequence between paclitaxel administration and a 10 Gy X-ray treatment did not influence TGD. Protocols with paclitaxel at 30, 45, or 60 mg/kg were combined with radiation treatments at various doses (from 10 to 65 Gy). Values of TCD50 varied from 50.8 Gy for X-ray alone to 31.8 Gy for paclitaxel 60 mg/kg + X-ray. No differences were observed among MDD of different protocols. CONCLUSIONS: These results suggest that, under some conditions, paclitaxel combined with radiation can show superadditive effects and this result combined with the lack of severe normal tissue damage indicate that a favorable therapeutic gain can be obtained.

First report of t(8;21)(q22;q22) in a case of de novo acute monoblastic leukemia.

Here we describe the case of a 30-year-old man with a diagnosis of de novo acute monoblastic leukemia (FAB M5a), whose karyotype analysis revealed the presence of the translocation (8;21)(q22;q22) as the sole chromosome anomaly. In spite of the rather good prognosis patients suffering from acute leukemia and carrying this translocation are supposed to have, our patient had a very poor outcome, including an early relapse resistant to any treatment and meningeal localization. Death occurred within 5 months from diagnosis. To our knowledge this is the first report of t(8;21)(q22;q22) in de novo acute monoblastic leukemia.