Malignant melanoma is considered unresponsive to conventional radiation therapy when it is delivered at a daily dose rate of 130–300 rad/fraction. Previous studies have suggested that this is in part due to a large shoulder on the radiation survival curve and that higher dose fractions might be beneficial. High-dose fraction therapy is effective for local control of cutaneous, lymph node, and soft-tissue metastases. Results in 46 patients treated with high- or low-dose fractions for intracranial metastases over the last decade in the Melanoma Unit and Department of Radiotherapy at Yale have been examined. Twenty-six patients received high-dose fraction therapy, generally 600 rad/fraction/week to 2400–3600 rad; 20 patients received low-dose fraction radiotherapy with 125–400 rad/fraction daily. All patients were given steroids, and most received chemotherapy. Results in both groups were similar. Comparison of high- and low-dose fraction patients revealed: improvement in 38 and 35%, respectively, stability in 23 and 25%, and deterioration in 38 and 40%. Median survival was three months in the high-dose fraction group and 21/2 months in the low-dose fraction group. Presence of hepatic metastases had no significant influence upon median survival in patients who received high-dose fraction radiotherapy. In patients receiving low-dose fraction, survival was 21/4 months with and three months without hepatic metastases. Death in most patients resulted from progression of central nervous system disease. Side effects, especially headache, were more prominent in the high-dose fraction group. However, in no instance did side effects require discontinuation of therapy. The greater ease of delivery for weekly high-dose fraction radiotherapy outweighed any other difference between the regimens.
A technique is described for opening the membrane of a red blood cell by electroporation in a manner which permits free exchange of the native hemoglobin with exogenous hemoglobin in the surrounding medium. After resealing the RBC's demonstrate near normal size and hemoglobin content and retain an effective methemoglobin reduction system. This method can be used to introduce natural or genetically engineered hemoglobins with altered oxygen binding characteristics. Allosteric effectors and other non-diffusible small molecules can be encapsulated during the same procedure. A fish Root effect hemoglobin exchanged into rat RBC's produced oxygen transport characteristics, unloading at high pressure at acidic pH, which should be useful to treat tissue hypoxia from a variety of causes.
Ninety-six patients with advanced squamous cell carcinoma of the head and neck were randomized to treatment with intravenous methotrexate followed by radical irradiation or radiotherapy alone. No significant differences were demonstrated in local disease control or actuarial survival rates at three and five years. Some patients with local treatment failure were surgically salvaged.
Cycloheximide (CHM) is a known inhibitor of cytoribosomal protein synthesis and has been shown to delay transit of mammalian cells through the cell cycle. Previous studies have shown modification by CHM of the effect of radiation both in vitro and in vivo. To investigate a possible protective effect of the drug on the radiation response of normal tissue, skin reaction and structural damage in the hind limbs were scored in CHM-treated rats exposed to single doses of X irradiation. The drug had no effect on radiation reaction when given immediately before or after X-ray treatment. However, protection against both skin reaction and structural damage was observed when CHM was given at least 6 hr prior to irradiation with maximal protection observed at 12 hr. A similar protective action was seen for the protein synthesis inhibitor emetine. If CHM or other inhibitors of protein synthesis interrupt the normal cell cycle with resultant selective radioprotection of normal tissue, they may enhance the therapeutic effectiveness of radiation. Cycloheximide (CHM) is a glutarimide antibiotic that has been shown to inhibit protein synthesis both in vitro and in vivo. It is known to be specific for cytoribosomal as opposed to mitochondrial protein synthesis, but there are conflicting reports in numerous plant and animal cell systems regarding the primary mode of action. The major inhibitory effect has been variously attributed to the initiation (1-3), elongation (4, 5), and termination (6) phases of messenger RNA translation. CHM has been reported to block transit of cells through the G1 (7) and G2 (8) phases of the cell cycle. It is hypothesized that the drug inhibits synthesis of a labile protein regulating growth (7, 9). Transformed tumor cell lines with defective growth control have been shown to be less sensitive to CHM-induced cycle arrest (10). The therapeutic effectiveness of ionizing radiation should be enhanced by agents which selectively increase the radioresistance of normal tissue without modifying the radiation response of tumor cells. The cell-cycle-active agents hydroxyurea (11 ) and cytosine arabinoside (12) have been shown to induce radioresistance in mouse intestinal cells, presumably at least partially on the basis of synchronization of cells into relatively radioresistant phases of the cell cycle. If CHM selectively modifies
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