Summary We determined the ability of the multidrug resistance (MDR) reversal agent cyclosporin-A to increase anthracycline drug accumulation in colorectal tumour cells in vitro, using the technique of on-line flow cytometry. Data of four previously untreated patients showed that cyclosporin-A can increase intracellular net-uptake of daunorubicin.A phase II study was initiated in 24 colorectal cancer patients. They received cyclosporin-A at a dose of 3 mg kg-' over 1 h as i.v. infusion, at 7 h and at 1 h preceding cytotoxic drug administration. At the end of the second cyclosporin-A administration epidoxorubicin 90 mg m-2 was administered as i.v. bolus. Cycles were repeated every 3 weeks. Median cyclosporin-A peak blood levels and levels at 18 h after cytotoxic drug administration appeared to be 6248ngml-' and 1012ngml-' respectively. Only one partial response was observed, despite these high cyclosporin-A levels. Cyclosporin-A did not cause major toxicity, only a 29% incidence of hot flushes was observed. Epidoxorubicin toxicities were as expected but the frequency of severe leucocytopenia was striking. This treatment schedule can not be considered active in colorectal cancer.
Ovarian cancer spreads early in the disease into the abdomen. An en bloc resection of the tumor, according to surgical principle, is not possible in patients with high-stage ovarian cancer. At surgery, large pelvic tumor lesions are found together with multiple tumor lesions involving the omentum, bowel, and mesentery together with a diffuse peritoneal carcinomatosis and diaphragmatic involvement. A multimodality approach with cytoreductive surgery and taxol platinum-based chemotherapy is therefore the mainstay of treatment of advanced ovarian cancer. The size of residual disease after surgery is one of the most important prognostic factors for survival. Patients with an optimal tumor cytoreduction (residual lesions smaller than 1 cm) have a significant longer survival (almost two times the median survival) than patients with larger residual lesions. This holds true even for patients with International Federation of Gynecology and Obstetrics (FIGO) stage IV disease. Patients in whom all macroscopic tumor is resected do have the longest survival. The 2-year survival of patients with a radical resection of all macroscopic tumors is 80%, in contrast to less than 22% for the patients with lesions larger than 2 cm. An optimal primary cytoreductive surgery can generally be performed in 30% to 50% of patients. Only in more experienced gynecologic oncology centers is the percentage as high as 85%, but sometimes at the cost of an increased morbidity and even mortality. The worse prognosis of the patients with a suboptimal primary cytoreductive surgery can be improved by an interval cytoreductive surgery after platinum-containing induction chemotherapy. The median survival and progression-free survivals are significantly lengthened by cytoreductive surgery. After more than 5-years follow-up there is still a significant survival benefit: the 5-year survival of the surgery patients was 24% versus 13% for the no-surgery patients (P = 0.0032). All patients, including those with unfavorable prognostic factors (stage IV disease, peritonitis carcinomatosis, or ascites at primary surgery), and even patients with stable disease after induction chemotherapy, seem to benefit from interval cytoreductive surgery. The increase in progression-free survival and overall survival does outweigh the morbidity associated with interval debulking surgery, which is not different from those associated with primary surgery.
Su_manr DNA adduct levels were measured with atomic spectroscopy in white blood cells (WBCs) from patients with sold tumours who were treated with six weekly courses of cisplatin. In 21 patients (I) the WBCs were collected after thawing frozen whole-blood samples according to a previously described method. In 32 other patients (II) WBCs were collected immediately after blood sample collection. The two methods for WBC collection were also compared in vitro. The maximal DNA adduct levels in vivo after the first course were in I 2.48 ± 1.14 and in 11 1.28 ± 0.40 pg of platinum per fig of DNA (P<0.0001). The DNA 'repair' in the first course (DNA adduct level at the end of the infusion minus the level 15 h post infusion) was in I 40% ± 29% and in 11 18% ± 29% (P = 0.009). These differences were consistent in all measured courses. In vitro, the DNA adduct levels in the freshly prepared WBCs were significantly lower at 0. 1 and 4. but not 24 h, after start of the incubation with cisplatin than in the WBCs collected after freezing and thawing the blood sample. The same experiment with carboplatin in vitro also resulted in significantly lower adducts in freshly isolated WBCs. The higher DNA adduct levels and DNA 'repair' in I are caused by remaining unbound cisplatin in the sample tubes, which can form DNA adducts ex vivo. The same results in vivo can be anticipated when carboplatin is used.
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