Treatment of solid P815x2 murine mastocytoma with adriamycin (NSC-1231127): toxity limitations.

The efficacy of adriamycin (NSC-123127), given as weekly or as 5-day-per-week doses, on the control of solid P815X2 murine mastocytomas was severely limited by hematopoietic and gastrointestinal toxicity. Although daily or weekly drug schedules both elicited dose responsiveness in terms of tumor control, no dose level of drug increased the life-span of tumor bearing animals.

Combined-modality oncotherapy with cyclophosphamide (NSC-26271) and radiotherapy: control of murine mastocytoma.

We investigated the effects of cyclophosphamide, alone and in combination with a 1,000-R/week radiotherapy schedule, on the growth of solid P815X2 tumors in 12-week-old male DBA/2 mice. Single-dose treatments of 150 mg cyclophosphamide/kg were given to animals bearing tumors of different ages. Such treatment of young tumors resulted in proportionately greater degrees of regression and steeper regrowth curves than did treatment of older tumors. Although slopes of regrowth curves differed greatly, time to regrowth (to pretreatment size) was the same for all age classes of tumors. Graded weekly exposures of 50-250 mg/kg for 4 weeks resulted in dose-dependent increases in incidence of complete remission, duration of remission (time to regrowth), and mean animal life-spans. The combination of radiotherapy to the tumor and 75, 150, or 225 mg cyclophosphamide/kg/week resulted in better local tumor control than occurred with radiotherapy or the drug alone. However, a dose-dependent increase in radiosensitivity of the gastrointestinal mucosa included in radiotherapy fields was observed. A 3-week course of radiotherapy plus 75 mg cyclophosphamide/kg/week (which is tolerated by the mucosa) increased animal lifespans to 165% of those of controls.

Control of local tumor growth with combined fractionated radiotherapeutic and chemotherapeutic regimens.

A treatment concept for the control of tumor growth utilized weekday radiotherapy and weekend chemotherapy. Mice were given sc injections of P815X2 mastocytoma cells on the lower back (day 0) and separated into the following treatment groups: 5-day/week X-irradiation, adriamycin alone at either 5 mg/kg body wt (days 6 and 13) or 2 mg/kg (days 5, 12, and 19), and combined radiotherapy and chemotherapy. Untreated controls had a mean tumor volume of 2.77 cm-3 and a mean survival time of 24 days. Adriamycin alone at 5 mg/kg resulted in an eventual tumor of 70 percent of the control value at death, whereas at 2mg/kg the tumor volume was 60 percent of control. After radiotherapy only, tumor size was 52 percent of control. Irradiation plus either 5 or 2 mg drug per kg body wt resulted in tumor volumes of 23 and 30 percent, respectively, of control values. Although no treatment regimen prolonged survival, the marked reduction in local tumor growth with combination therapy indicates that it may be a useful concept in future cancer therapy.

Influence of adriamycin and adriamycin-radiation combination on jejunal proliferation in the mouse.

The influence of adriamycin and adriamycin-radiation combinations on posttreatment proliferative activity of the mouse jejunum was examined by measuring [3H]thymidine incorporation. Single doses of 5 or 10 mg/kg produced a transient reduction in the proliferative activity, while 1 mg/kg had little effect. After 10 mg/kg, there was a rapid decrease in the number of mitotic figures, followed by a gradual decrease in the number of and rate of DNA synthesis in S-phase cells. A compensatory epithelial hyperplasia characterized by an enlarged crypt proliferative population and shortened mitotic cycle duration was observed beginning 48 hr after treatment. Multiple doses of adriamycin totalling 10 mg/kg inhibited cell production to a greater extent than the equivalent single dose. In combination with 1000 R, adriamycin (5 mg/kg) given from 96 hr before to 72 hr after irradiation reduced the amount of postirradiation proliferation.

Intestinal cell proliferation during fractionated abdominal irradiation.

In the mouse, at normal steady state of cell proliferation, the compensatory proliferative response to intestinal irradiation is such that when radiation exposures totalling 1,000 R are concentrated over the first few days of the week, summated proliferative activity for the entire week is near control levels. Symmetrically distributed exposures over a five-day treatment week (200 R daily, and especially 333 R on Monday, Wednesday and Friday) result in depressed levels of overall weekly proliferation. In these instances, the weekend break is particularly crucial. Similar results were obtained when the one-week measurement period was inserted between the third and fifth week of abdominal therapy, except in this instance, 200 R per day did not result in sub-control levels of proliferation, whereas 333 R on M, W and F, continued to do so. The intestine seems able to maintain its barrier epithelium for extended periods of diminished cell input, provided such is not too severe and that it seems from decreased cell production rate per crypt rather than from crypt attrition. A partial explanation for this relative tolerance is given by the finding that the vast majority of proliferative cells, even those irradiated and rendered permanently incapable of further division, succeed in migrating up the villus and hence help to maintain a barrier epithelium. In that sense, nearly all cell divisions become useful, even in the face of repeated exposures.

Time/dose relationships in abdominal irradiation: a definition of principles and experimental evaluation.

We have drawn upon the work of numerous investigators to formulate a model describing the principles governing the acute response of the intestinal epithelium to cytotoxic agents. Tolerance (exposure required to kill 50 per cent of the animals) to abdomen-only irradiation was measured experimentally in the mouse using a total of 17 time/dose fractionation schedules. The principle determinants of intestinal response to fractionated radiation therapy were magnitude of each fraction and the introduction of regular recovery intervals during the course of treatment. The roles of exposure per week, exposures per day, and radiation days per week were also examined. The log-log plots of endpoint v. either number of fractions or overall treatment time yielded straight lines with slopes of 0 with 54 and 0 with 59 and y intercepts of 1,270 and 812 rets respectively. The single dose for 50 per cent acute intestinallethality (LD50/6 days) was 1,610 R. It would appear that the acute intestinal tolerance to fractionated irradiation is, in the mouse, extremely dependent upon fraction number and overall treatment time. The biological basis for intestinal tolerance to cytotoxic agents is discussed in light of the results of these studies and the model initially described.

Damage and recovery assessment of the mouse jejunum to abdominal X-ray and adriamycin treatment.

The influence of adriamycin on the post-irradiation proliferative response of the mouse jejunum was examined. Doses of either 5 or 10 mg/kg of adriamycin administered immediately after abdominal irradiation reduced the LD50/7 days by 300-400 R. Neither dosage of the drug reduced the number of surviving crypts, as measured by the crypt isolation and microcolony techniques, for a given radiation exposure. However, both drug dosages reduced the amount of post-irradiation compensatory hyperplasia, as measured by 3H-thymidine incorporation.