Larry L. Schenken

Response of the murine gastrointestinal epithelium to cis-dichlorodiammineplatinum II: Radiation combinations

Single doses of cis-dichlorodiammineplatinum II (cis DDP) up to 8 mg/kg produced a dose-dependent inhibition of proliferative activity with a subsequent period of compensatory hyperplasia in the colon. The stomach was less responsive to cis DDP. Cis DDP-radiation combinations produced a dimunition in the proliferative response of the colon when compared to that following radiation only. This response was only seen in the stomach following 8 mg/kg of cis DDP and radiation. Cytokinetic analysis of the jejunal response to 8 mg/kg of cis DDP showed a gradual reduction in LN and MF/crypt with a reduction in the rate of DNA synthesis of S-phase cells through 8 hours post-treatment. By 24 hours the cellular DNA synthetic rate had recovered, although the number of S-phase cells was further reduced. The previously reported jejunal response to cis DDP-radiation combinations involved a reduction in crypt survival, coupled with a reduced proliferative capacity of surviving cells. Further investigation has revealed a possible inhibition of radiation damage repair by cis DDP, leading to increased levels of cell kill with the combination and reduced recovery of DNA synthetic rates in surviving cells.

The Modification of Gastrointestinal Tolerance and Responses to Abdominal Irradiation by Chemotherapeutic Agents

Groups of male DBA/2 mice were irradiated with partial abdominal exposures of x radiation ranging from 100 to 1,600 rads. Concomitant with radiation exposure and at 1 or 4 hours prior to, and at 1, 6, 24, or 48 hours after irradiation, various chemotherapeutic agents were administered, i.e., methotrexate, Cytoxan, adriamycin and BCNU. The results suggest that excessive gastrointestinal toxicity may result if aggressive chemotherapy is closely spaced with radiation exposure for the treatment of abdominal neoplasms. However, adjustment of dose and time patterns based on the proliferative responses of the mucosa may circumvent such toxicity to a large extent.

Therapeutic potentiation of combined cis-dichlorodiammineplatinum (II) and irradiation by ICRF-159.

Abstract The effect of fractionated ICRF-159 (25 mg/kg, g3h×4) pretreatment on the antitumor activity of cis DDP+irradiation combinations has been evaluated using the Lewis lung tumor. All three agents given alone as single treatments result in transient interruption of proliferative activity with only slight to moderate alterations of tumor growth. Fractionated ICRF-159 treatment, while eliciting low cytotoxicity, results in a partial cytokinetic redistribution of tumor cells enhancing subsequent radiotherapy and chemotherapy with cis DDP. For cis DDP-radiation combinations, where cis DDP precedes irradiation, increasing the intertreatment time from 6 hr to 24 hr results in synergistic interactions and increased treatment efficacy. When cis DDP-radiation combinations followed fractionated ICRF-159, regression was greatly enhanced suggesting that relatively non-cytotoxic agents may be used to sensitize low growth fraction, resistant tumors to subsequent combined-mode therapy.

Time/Dose Relationships in Experimental Radiation Cataractogenesis

The response of the mammalian lens to fractionated radiation exposures was evaluated as a model system for predicting delayed radiation effects on normal tissue. Only the heads of male Ha/ICR mice were irradiated with 14 different time-dose schedules and followed for cataractous changes. A log-log plot of dose vs time yielded a line with a slope of 0.303 and ordinate intercept of 1050 R; a similar plot for dose vs fraction number yielded a slope of 0.382 and ordinate intercept of 835 R. Results suggest that the lenticular response to radiation may be a useful model for studying late effects.

Serum tumor markers in non-small cell lung cancer. A comparative analysis

Background. The role of serum tumor markers in non‐small cell lung cancer (NSCLC) remains undefined. New proposed markers have seldom been rigorously compared with existing standards. The authors prospectively compared the performance of three new monoclonal antibodies (MoAb) (5E8, 5C7, and 1F10) with the established serum markers carcinoembryonic antigen (CEA) and squamous cell carcinoma antigen (SCC).

The cytokinetic basis for the design of efficacious radiotherapy protocols

Abstract Studies were performed to investigate the perturbing effects of ionizing radiations on the cell kinetics of T1699 transplantable mouse mammary tumors (MMT). Cell kinetic parameters included the 3H-TdR labeling index (LI), the DNA synthesis time (TS) and the primer dependent DNA polymerase labeling index (PDPI), an estimate of tumor growth fraction; they were determined by in vitro methods at various times after acute (400–1200 R) and fractionated (1000 R) X-irradiation. The cell kinetic response after both acute and fractionated treatment was generally similar and could be divided into four phases. (1) The initial phase of the response, occurring within the first 24 hr, was characterized by a decrease in 3H-TdR LI, an increase in PDPI and a concomitant lengthening of the TS. (2) The second phase was characterized by a variable, dose dependent interval of decreased cellular proliferation, as evidenced by a lengthening of TS and decreases in both PDPI and 3H-TdR LI. (3) The third phase of the response, the recovery phase, was characterized by increased cellular proliferation as evidenced by the recovery of TS to normal and increases in both PDPI and 3 H-TdR LI to above control levels, in most cases. (4) The fourth phase of the response was characterized by a reestablishment of normal proliferative patterns. Studies with continuing radiotherapy schedules showed that the most effective schedules for local control and ILS were those in which radiation fractions were given just prior to initiation of observed proliferative recovery. The least effective schedules were those in which radiation fractions coincided with the time of maximal proliferative activity.

Responses of an experimental solid tumour to irradiation: A comparison of modes of fractionation.

Several radiotherapeutic schedules compatible with continued structural-functional integrity of the gastrointestinal (GI) mucosa were compared utilizing the P815X2 murine mastocytoma grown as a solid subcutaneous tumour. Both the tumour and underlying normal tissues were irradiated during the treatments. The tumour exhibited a Do that increased from 210 rad to 397 rad as the tumour aged and in all instances demonstrated minimal shoulders in survival curves. In spite of a relative radioresistance of cells within the solid tumour, quite effective control of localized disease could be accomplished with radiotherapy schemes compatible with GI tolerance limits. Schedules evaluated utilizing this model included acute exposures to 1122 rad, daily exposure to 187 rad, 5 days/week exposures to 281 rad, twice weekly exposures (561 rad on Mondays and 374 rad on Thursdays) and a high dose, two fractions per day, schedule. Tumours were followed for changes in growth patterns during these schedules. Efficacy of tumour control was determined and schedules were compared on this basis. Aggressive radiotherapy approaching the tolerance limits of any of the fractionation schemes proved most effective.

Digestive Tract Cell Proliferation and Food Consumption Patterns of Ha/Icr Mice

The relationship between the daily pattern of food consumption and the proliferation rate of the qesophagus, stomach, forestomach, small intestine and colon of Ha/ICR mice was examined. Proliferative activity was determined by [3H]TdR incorporation on a wet weight tissue basis, along with selective counting of labelled nuclei. Under conditions of ad libitum feeding with a 12 hr light cycle (lights on at 0600) mice eat most of their food during the dark period. A distinct circadian rhythm was observed in the oesophagus, stomach, forestomach and colon with the peak of [3H]TdR incorporation between 0400 and 0600 and the nadir between 1600 and 1800. Although a circadian fluctuation was observed in the small intestine, its amplitude was much less than in other areas. This rhythmic change in proliferation rate could be phase shifted by allowing the mice to feed only between 0800 and 1600 for 14 days. Under these conditions the peak in proliferative activity occurred between 1800 and 2000. Fasting reduced the daily level of proliferative activity in all of the digestive tract sites studied, and for all areas except the oesophagus greatly reduced or eliminated the circadian fluctuation. the forestomach and colon were the most influenced by fasting with 24 hr [3H]TdR incorporation reduced to 30–40% of the control value. Refeeding following a 48 hr fast produced a rapid increase in proliferative activity peaking at levels well above the control value at 16 hr after the onset of refeeding. the major exception to this was the small intestine which slowly returned to the control value during the first 24 hr. Partial refeeding produced a diminished refeeding response. Once the normal pattern of food consumption was re‐established following refeeding the normal proliferative fluctuations were again observed.

Adriamycin-radiation combinations: Drug induced delayed gastrointestinal radiosensitivity

Abstract The administration of Adriamycin (ADR) results in acute short-term reductions in cell production within the gastrointestinal mucosa. Interactions between ADR doses and radiation appear minimized as the intertreatment time interval expands to five days. However, as the times between drug administration and abdominal radiation exposure are further lengthened (from 14–49 days), a progressively severe defect in postirradiation mucosal cell production is noted. Although the mucosa appears normal histologically and crypt cell cellularity and cell production are normal, the proliferative response following radiation is reduced by as much as 50% if ADR is given 7 weeks prior to the radiation exposure. We postulate that this effect is a manifestation of latent damage to the stem cell compartment within the crypt or that secondary support systems such as mucosal vascularity have been compromised by ADR.

ICRF-159 enhancement of radiation response in combined modality therapies. I. Time/dose relationships for tumour response.

The combined effect of the chemotherapeutic agent ICRF-159 and irradiation were evaluated using the Lewis lung tumour (LL). At a daily dose of 25 mg/kg, ICOF given alone prevented the progressive growth of LL. Daily pretreatment also potentiated the effects of radiation (600 rad) on tumour growth, provided the pretreatment kinetics of the tumour permitted a response to radiation alone. Single acute doses of the drug failed to alter the growth of LL, and when combined with radiation failed to enhance the radiation effect. Fractionation of the drug (25 mg/kg; 4 doses at 3h intervals) before irradiation, however, results in immediate effects on tumour growth which are more than additive. The results suggest that a low dose of ICRF-159 for extended periods is more effective in enhancing radiotherapy than a high dose provided acutely.