bietaserpine and Fibrosarcoma

The toxicity of 1-[2-(diethylamino)ethyl]reserpine (DL-152) has been measured for 4 transplantable mouse tumors. DL-152 was found to be toxic to cells of all the tumor models tested (KHT fibrosarcoma, RIF-1 fibrosarcoma, EMT-6 adenocarcinoma and Lewis lung carcinoma) when the drug was given by intraperitoneal injection to the tumor-bearing mouse and cell survival was measured by excision assay. For the KHT tumor, hypoxic cells were found to be more sensitive to the drug in vivo than were aerated cells, and a similar response to hypoxia was observed in vitro, suggesting that sensitization occurred at the cellular level. Neither EMT-6 nor RIF-1 tumors showed increased sensitivity to the drug when cells were exposed under hypoxic conditions in vivo or in vitro. However, when the response of aerated cells of the 3 tumors was compared, the relative sensitivities for tumors exposed in vivo did not show the same ranking as the results of in vitro toxicity assays. This difference in in vitro and in vivo response in the different tumor models did not appear to be related to pharmacokinetic factors since the maximum tissue concentration and the rate of clearance of the drug were similar for all the tumors studied.

Topics: Adenocarcinoma; Aerobiosis; Animals; Carcinoma; Female; Fibrosarcoma; Lung Neoplasms; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred C57BL; Neoplasm Transplantation; Reserpine; Tumor Cells, Cultured; Tumor Stem Cell Assay

Topics: Animals; Antineoplastic Agents; Cell Survival; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Fibrosarcoma; Male; Mice; Mice, Inbred C3H; Oxygen Consumption; Radiation-Sensitizing Agents; Reserpine

The protective effect of pre-irradiation injections of diethylaminoreserpine (DL-152) for normal and malignant tissues in the mouse has been investigated. Dose modifying factors (DMFs) obtained for normal tissue ranged from 1.0 for bone marrow CFUs to more than 1.8 for skin. The DMFs for two transplantable tumours investigated were 1.0 for the EMT6 adenocarcinoma and 1.70 for the KHT fibrosarcoma (at a surviving fraction of 0.1. Acutely hypoxic KHT tumours were protected to a slightly lesser extent than were aerated tumours. For the KHT tumour, the number of clonogenic cells recovered from non-irradiated tumours one hour after DL-152 injection was reduced to 60 per cent of the number covered fro saline-injected controls, while, if DL-152 injected mice were acutely hypoxic at the time of sacrifice, the number of clonogenic cells was further reduced. The survival of non-irradiated EMT6 tumour cells was unaffected by DL-152 injection prior to sacrifice.

Topics: Adenocarcinoma; Animals; Antihypertensive Agents; Cell Survival; Fibrosarcoma; Hematopoietic Stem Cells; Male; Mammary Neoplasms, Experimental; Mice; Radiation-Protective Agents; Reserpine; Sarcoma, Experimental; Skin

Diethylaminoreserpine (DL-152), an inhibitor of cyclic AMP phosphodiesterase, has been shown to kill clonogenic cells of the KHT fibrosarcoma when the drug is given intraperitoneally to the tumour-bearing mouse. DL-152 shows a greater toxicity to acutely hypoxic cells than to aerated cells. Following DL-152 injection, the number of surviving clonogenic tumour cells fell progressively until a minimum level was reached at 48 h after injection; repopulation commenced immediately and proceeded rapidly. The extent of cell killing following DL-152 injection was directly proportional to the size of the tumour at the time of treatment. A single injection of DL-152 produced no measurable change in the growth rate of small tumours. Treatment of larger tumours however, induced a period of slow growth followed by a return to the rate of growth observed in controls.

Topics: Animals; Cell Survival; Clone Cells; Female; Fibrosarcoma; Male; Mice; Mice, Inbred C3H; Reserpine; Sarcoma, Experimental