Joella F. Utley

Radioprotection of tumor and normal tissues by thiophosphate compounds

The efficacy of the radioprotective thiophosphate compounds WR638 (sodium hydrogen S‐[2 aminoethyl] phosphorothioate) and WR2721 (S‐2‐[3‐amino‐propylamino] ethyl phosphorothioate) was determined for a wide range of normal tissue and tumor endpoints. Dose‐modifying factors (D.M.F.) were obtained for mouse skin, small intestine, bone marrow, esophagus, lung, and kidney. D.M.F. values were also obtained for the P‐388 leukemia, the EMT‐6 mouse mammary carcinoma assayed in vitro, and the EMT‐6 mammary carcinoma assaysed for cure. The D.M.F. values obtained for normal tissue ranged from 1.2 for lung to 3 for bone marrow CFUs. The D.M.F. values for tumor ranged from 1.3 for cure of the EMT‐6 carcinoma to 2.2 for mean survival time in the P‐388 leukemia. There appears to be a decreasing dose‐modifying factor as a function of increasing dose in both tumor and normal tissue systems. The degree of protection afforded tumors appears to relate to their vascularization and their anoxic cell component. Although the D.M.F. obtained for cure of the solid EMT‐6 carcinoma would appear to be lower than for normal tissues with single doses, the data presently available do not allow one to predict that such a beneficial effect would occur with the multiple small doses used clinically.

High-dose-rate afterloading brachytherapy in carcinoma of the uterine cervix

The Brachytron has been used in the University of California at San Diego Medical Center since 1970 as one method of treating gynecological malignancies. This machine contains a high intensity cobalt 60 remote afterloading cycling source used for intracavitary brachytherapy. One hundred twenty-seven patients with epithelial carcinoma of the cervix are available for analysis of 5-year survival, and 176 are analyzed for treatment complications two years following therapy. Five year survival figures for FIGO-staged patients treated with external beam pelvic irradiation and intracavitary Brachytron treatments are as follows: Stage I, 89%; Stage II, 58%; Stage III, 33%, and two of five patients Stage IVa. Rectal complications graded moderate or severe (M, S) were dose-related and gradually decreased over the years as techniques improved. Complications from early results in 1970-1972 (24% M, 10% S) were reduced to lower levels in 1976-1979 (14% M, 4% S). The Brachytron offers the advantage of rapid dose delivery. Thus, patients can be treated in an outpatient setting, avoiding the cost of hospitalization and the risks of anesthesia. The Brachytron also offers virtually complete radiation safety to all attending medical personnel. With survival and complication figures similar to those reported for patients treated with conventional low-dose-rate brachytherapy, the Brachytron represents an effective alternate mode of therapy for uterine carcinoma.

Response of a Murine Solid Tumor to In Vivo Combined Chemotherapy and Irradiation

The EMTG murine solid tumor was employed to examine the combined effect of gamma irradiation and chemotherapy. A dose of cyclophosphamide, actinomycin D, BCNU, and bleomycin A2, selected to yield a 10% survival fraction when given singly, was administered 2 hours before single graded doses of whole-body irradiation and the results compared to a radiation-only dose-response curve. Bleomycin A2 and BCNU modified the shoulder region of the curve. Actinomycin D was less than additive in the hypoxic region of the curve, while cyclophosphamide was simply additive throughout the curve, suggesting that it killed both well-oxygenated and poorly-oxygenated tumor cells in similar proportions.

Differential radioprotection of euoxic and hypoxic mouse mammary tumors by a thiophosphate compound.

The radioprotective drug S-2-(3-aminopropylamino) ethyl phosphorothioate (WR2721) was evaluated in the EMT-6 mouse mammary tumor. Under euoxic conditions (DMF approximately 2), the drug protected the oxygenated portion of the tumor but not chronically hypoxic cells. Acutely hypoxic cells were protected to a slight degree. Since WR2721 has been shown to protect normal tissues with a DMF of 2–3, it is likely that decreased protection of anoxic tumor cells will be clinically useful.

Protection of normal tissues by WR2721 during fractionated irradiation

Abstract The radioprotective effect of S-2-(3-aminopropylamino)ethyl phosphorothioate (WR2721) was studied in two normal mouse tissues-skin and small intestine—that were given single and fractionated doses of 137 Cs radiation. A total of two-thirds of the toxic LD 50 of WR2721 could be given before single-dose irradiation. However, toxicity increased when the same drug dose was given in two or more fractions before split-dose irradiation: less than one-half of the single drug dose could he administered safely. In the skin, WR2721 was slightly less protective with fractionated irradiation (DMF = 1.3–1.5) than with single-dose irradiation (DMF = 1.5–1.7). The DMF decreased with increased radiation dose in both cases. In the small intestine, WR2721 protection was essentially the same with single-dose irradiation (DMF = 1.6) and fractionated doses (DMF = 1.7). This degree of radioprotection in skin and intestine, in spite of a greatly reduced drug concentration, supports the possibility of clinical use.

Approaches to Optimization of Dose in Radiation Therapy of Cervix Carcinoma

A treatment planning approach to radiation therapy for carcinoma of the cervix which attempts to maximize tumor dose and minimize the effect on normal tissue must include additonal dose reference points besides the standard ones (Manchester points A and B, mg-hrs.) A variety of loading configurations can be used to treat the tumor volume to a specified dose. In order to avoid inappropriate loading arrangements, dose at the tumor and at the vault must be carried to required therapeutic levels.

Radiosensitization of normal tissue by chloroquine.

Severe radiation reaction with chest wall necrosis occurred following 5,000 rads of 60Co irradiation. The patient was arthritic and on chloroquine therapy. This delayed reaction was due to chloroquine radiosensitization. Rats treated with combined chloroquine and chest wall irradiation were compared to rats receiving irradiation alone. The acute radiation reaction was greater in the drug treated animals.

Carcinoembryonic Antigen and Skin Test Reactivity in Tumor Radiotherapy

Serial carcinoembryonic antigen (CEA) levels were obtained from 122 cancer patients. In a random selection, the levels in 67 of these patients were compared with clinical response to radiotherapy. Skin tests were also performed for histoplasmin, tuberculin and mumps. CEA levels, skin-delayed hypersensitivity reaction (DHR) and clinical tumor response were evaluated and correlated. Clinical response of tumors to radiotherapy was more often seen in patients with positive skin tests, but no correlation was observed between skin test reactivity and CEA response curves.