Cancer chemotherapy reports最新文献

Adriamycin and DTIC were used in combination because of their reported effectiveness in neuroblastoma when administered as single agents and because of the poor survival rate of patients with this malignancy in its disseminated stage. Eighteen patients with previously treated stage IV neuroblastoma received this combination chemotherapy every 21 days. Two to eight courses were administered. Two partial and no complete remissions were seen. Mild to moderate gastrointestinal and hematologic toxicity was observed.

Cyclophosphamide and isophosphamide (an analog) were tested for their effect on the antilymphoma allograft reaction in normal and lethally irradiated mice. Both drugs were effective in abrogating the classic allograft response if given 1 or 3 days before the tumor challenge. While the drugs also inhibited the hemopoietic-histocompatibily response, they were effective when adminstered 7 days before challenge. It is suggested that the activity of various immunosuppressive agents could be compared for their effect on the hemopoietic-histocompatibility system to select the best agent for transplantation of bone marrow or bone marrow or bone marrow-derived cells. Drug toxicity, as well as the effect of the drugs on humoral response and DNA synthesis, was also compared. While isophosphamide was found to be less toxic than cyclophosphamide, the effect of humoral response and DNA synthesis was comparable.

The murine C1300 neuroblastoma model has been evaluated as a possible model for children with widespread metastatic disease. Drug toxicity studies were conducted in adult A/J mice with various doses of antitumor agents. Adriamycin, BCNU, bleomycin, guanazole, acronycine, isophosphamide, DTIC, ICRF-159, cyclophosphamide, vincristine, and vinblastine were adminstered intraperitoneally to random groups of normal mice. After identification of appropriate doses, chemotherapy studies were conducted with varius regimens of drugs. Chemotherapy was administered to adult A/J mice when their subcutaneously implanted tumors measured 1.0-1.7 cm in diameter. Antitumor drugs can be classified into three groups according to drug efficacy. BCNU, cyclophosphamide, and isophosphamide were extremely active. Cytosine arabinoside was reported to be active against this murine tumor in a previous publication. Drugs with minimal activiyt which deserve further evaluation included adriamycin, guanazole, ICRF-159, DTIC, and vinblastine. Inactive drugs were acronycine, bleomycin, 5-fluorouracil, and vincristine. These experiments suggest that children with metastatic neuroblastoma may respond to cyclophosphamide, isophosphamide, and BCNU, while DTIC, adriamycin, ICRF-159, guanazole, and the vinca alkaloids may also be effective. The results suggest that agents selected by the C1300 model should be given adequate clinical trials.

Dibromodulcitol and cyclophosphamide are both alkylating agents. In this study, these two drugs were compared for their effectiveness as remission maintenance therapy for childhood acute lymphoblastic leukemia or acute undifferentiated leukemia. Toxic effects were similar in both groups of patients although cystitis did not occur with the dibromodulcitol treatment. The duration of remission was slightly shorter for dibromodulcitol than for cyclophosphamide (P = 0.04). There was, however, a lower incidence of CNS leukemia in the patients treated with dibromodulcitol, which did not seem to be related to a basic difference in the patient groups.

An initial clinical phase I trial of isophosphamide has been carried out at dose levels of 200-10,000 mg/m2 of body surface area using a single-dose, every-3-week schedule. Significant toxicity was not seen at isophosphamide dose levels less than 2900 mg/m2. At higher doses, nausea and vomiting was nearly universal. Hematologic toxicity manifested by leukopenia occurred in 12 of 20 patients treated with doses of 3800-7000 mg/m2. Thrombocytopenia to 100,000 platelets/mm3 was not seen in any patient. Urinary bladder toxicity manifested by hemorrhagic cystitis was seen in 15 of 23 patients treated with doses of 3800-10,000 mg/m2. Hemorrhagic cystitis could be completely prevented by bladder irrigation with N-acetyl-L-cysteine (1% solution, 2000 ml/day). With careful attention to hydration, renal toxicity was largely prevented with blood urea nitrogen elevations to 30 mg/dl in only two of 14 patients receiving isophosphamide doses of 5000-7000 mg/m2. Another side effect was central nervous system toxicity in seven of 17 patients at doses of 5000-10,000 mg/m2. For phase II trials a dose of 5000 mg/m2 is recommended, with careful attention to the state of hydration in the patient and with the knowledge that bladder irrigation may be necessary for the prevention and/or amelioration of bladder toxicity.

The systematic chemical control of cancer requires a quantitative knowledge of the pharmacologic disposition of antitumor drugs in both healthy and malignant tissues in the body. Pharmacokinetic models can predict the drug concentration in both tumor sites and healthy organs and hence may provide a predictive capability regarding both antitumor action and concomitant toxicity. Adriamycin is an anthracycline antibiotic that has been demonstrated to possess a broad spectrum of antitticularly solid tumors. Its major toxicity is manifested by the depression of normal cell proliferation in the bone marrow and a delayed dose-dependent cardiac toxicity eventually resulting in congestive heart failure. This study is concerned with the development of a predictve analytic model for the pharmacokinetics of adriamycin. The analytic approach embodies a physiologic multicompartmental model as a framework. This model postulates that specific organs or tissue masses may be simulated by a compartment whose elements consist of physiologic properties such as tissue volume and blood flow and pharmacologic behavior such as tissue binding and metabolic activity. A mass balance is set up across each compartment and all compartments are linked by an independent blood compartment. The mass balance includes terms representing inflow and outflow of the drug as well as its metabolism, protein-binding, and other pharmacologic behavior. A model has been developed that has ten compartments which represent the plasma, heart, liver, kidney, lung, lean tissue, adipose tissue, gut, bone marrow, and spleen. Solutions of the system of equations yield the time course of the drug in each organ. Predictions of adriamycin concentration-time curves in the ten tissues after intravenous (iv) administration were generated using this model. With few exceptions, agreement between predicted and actual tissue data in rabbits was excellent. Human plasma levels of adriamycin were predicted and comparison with patient data demonstrated a reasonable first approximation.