Potentiation of X-Ray Effects by Actinomycin D

X-ray effects on normal tissues have been enhanced by combining roentgen irradiation with the intravenous administration of actinomycin D (1, 2), an antibiotic and carcinolytic agent isolated by Waksman (3, 4). Encouraging responses to this form of combined therapy have also been noted in a variety of neoplasms (1). One hundred and twenty-six children and adults have received 220 courses of this form of treatment at The Children's Cancer Research Foundation of The Children's Medical Center in Boston. The clinical observations to be described are based on experience with these patients. The effects of combined therapy on normal tissues are: 1. Early erythema in the therapy portal after skin doses (including exit dose) of 350 r or less. Comparable responses after irradiation alone usually require skin doses of about 1,200 r. 2. Similar enhanced responses are obtained in the buccal and pharyngeal mucosa of patients receiving x-ray treatment to the head and neck. 3. The time required for progression of these radiation reactions in the skin through the usual stages of erythema, tanning, desquamation, and complete healing is reduced to four to six weeks rather than the two to three months usually elapsing following x-ray alone. 4. Actinomycin D therapy alone can reactivate “latent” radiation effects in normal tissues. For example, in skin previously irradiated but normal in appearance an erythema may develop during actinomycin D therapy, identical in type to that produced by roentgen irradiation. This response is sharply restricted to the areas previously treated by x-rays. The severity of the reaction varies from a mild reddening to pronounced desquamation. It is most accentuated when only a brief interval separates the courses of radiotherapy and chemotherapy. 5. These enhanced effects can lead to dangerously severe local reactions if high doses of each agent are used together or successively, or should a patient prove to be especially sensitive to the combination. In order to study these reactions further, the effects of combined treatment on the skin of normal mice were examined. Groups of normal healthy CAF mice, approximately 20 gm. in weight, were selected. Actinomycin D was given intravenously or intraperitoneally in single doses of 150 µg./kg. or in similar amounts daily for three days. The radiation factors were: 250 kv (constant potential), 15 ma, 40 cm. T.S.D., 1 mm. A1 (added filtration), h.v.1. 0.63 mm. of copper. The output at 40 cm, was 247 r per minute. The animals were shielded from the direct beam and from back-scatter by appropriate lead, only the right rear legs being included in the beam. The doses given were 1,000 r (air) in one exposure or 1,200 r (air) in three days (400 r daily). The following observations were made: 1. There were no pathological changes produced in the skin of mice receiving only actinomycin D. 2. Earlier and more consistent epilation appeared in mice treated with x-rays combined with actinomycin D than in those treated only with x-rays.