Mammary carcinogenesis-enhancing effect of adrenalectomy in irradiated rats with pituitary tumor MtT-F4.

Mammary carcinomas were found at autopsy 98--100 days after irradiation in 12 of 14 (86%) multiparous Fischer female rats which had been adrenalectomized and given grafts of secretory pituitary tumor strain MtT-F4 soon after exposure to gamma-rays or fission neutrons. A single carcinoma was found in 1 of 10 unirradiated, MtT-bearing, adrenalectomized animals. When adrenalectomy was not done, no tumors were found in 8 unirradiated or in 13 irradiated MtT-bearing rats rats. In view of the well-established finding that Cortisol is essential for milk production, we suggested as a working hypothesis that, in the presence of high titers of mammotropic hormone and adrenal corticoids, differentiation of a given cell for milk secretion reduced that cell's proliferative potential. When such differentiation was precluded by adrenocorticoid deficiency, more irradiation-altered mammary epithelial cells retained their high proliferative potential and contributed to carcinoma formation.

Effects of grafts of single anterior pituitary glands on the incidence and type of mammary neoplasm in neutron- or gamma-irradiated Fischer female rats.

Three batches comprised of 48 young adult Fischer female rats each were subjected to total-body irradiation with 50 rads modified fission neutrons, or were given 600 rads 137Cs gamma-rays, or served as unirradiated controls. On the day following exposure, one-half of each batch was grafted with a single anterior pituitary gland beneath the left kidney capsule. The animals were observed for mammary neoplasia and all those that died during the experiment were autopsied. The experiment was terminated 538 +/- 13 days after irradiation when all neutron-irradiated, pituitary-grafted animals had one or more mammary tumors. Only 2 of the 23 untreated rats that survived until termination of the experiment developed mammary fibroadenomas, and none had mammary carcinomas. The incidence of fibroadenomas was increased, and a single carcinoma was found, in unirradiated rats with pituitary grafts. Irradiation alone caused an increase in the incidence of mammary fibroadenomas and the appearance of carcinomas. Fibroadenomas were markedly increased by the addition of pituitary grafts to irradiation. Carcinoma incidence was less markedly affected. The neutron dose of 50 rads was slightly more effective in inducing mammary neoplasms than the 600-rad dose of gamma-rays.

Calcitonin as an indicator of the response of human small cell carcinoma of the lung cells to drugs and radiation.

A calcitonin (CT)-producing cell line (DMS53) established from human small cell carcinoma of the lung was grown as three-dimensional multicellular spheroids in spinner culture or on agar in multiwells, and as tumors in nude (athymic) mice. CT release into the media was directly proportional to spheroid volume. The response of these cells following exposures to X-irradiation, Adriamycin, or diazoacetylcholine iodide was assessed by monitoring levels of CT released into the media by individual spheroids. Levels of CT in the blood of nude mice bearing DMS53 xenografts were directly proportional to tumor volume and decreased proportionally with tumor response to X-irradiation and cisplatin treatment. These results suggest that the DMS53 spheroid and xenograft models may be useful systems to monitor responses to therapy utilizing CT as an indicator of tumor burden.

Carboplatin as a potentiator of radiation therapy.

A rationale for coordinating the administration of carboplatin with radiation to achieve enhancement of cancer therapy is developed. This approach is based upon a review of the reports of effects in a variety of systems, effects attributed to interactions between cisplatin or other platinum analogs and radiation. Two major effects include radiosensitization (RS) of hypoxic cells with platinum present during irradiation and potentiation of cell kill with platinum complexes administered after irradiation. Both these effects are expected to result in an improved therapeutic ratio. The latter effect may include inhibition of recovery from radiation-induced potentially lethal damage (PLD) and sublethal damage (SLD). Evidence for RS by carboplatin with an enhancement ratio (ER) of 1.8 is presented in Chinese hamster lung cells (V79) irradiated in culture under hypoxic conditions. Potentiation of radiation therapy in mice bearing a transplanted mouse mammary tumor (MTG-B) is reported as a supra-additive tumor growth delay when 60 mg/kg carboplatin is administered either 30 minutes before or immediately after 20 Gy of X-irradiation. Improved efficacy resulting from ongoing clinical trials coordinating cisplatin with radiation should support the role for carboplatin as a potentiator of radiation therapy since this second generation complex of platinum also interacts with radiation and larger concentrations of platinum should be attainable in tumors using the new drug.

Enhancement of the potentiation of radiotherapy by platinum drugs in a mouse tumor.

This study examines two ways to enhance cisplatin-mediated potentiation of the radiotherapy of a mouse mammary tumor, MTG-B: a) the appropriate sequencing of the two modalities, and b) the use of platinum "rescue" at appropriate times relative to injection of cisplatin to ameliorate platinum toxicity and permit the use of larger concentrations of cisplatin. Reduced TCD50 values and potentiated tumor regression resulted when cisplatin preceded irradiation by 1 hr compared to injection of cisplatin post-irradiation. Cisplatin "rescue" was demonstrated by DDTC, WR-2721 and 5-TG, and enhanced effects on the inhibition of tumor growth resulted when 20 mg/kg cisplatin and 730 mg/kg DDTC were combined with radiotherapy.

Enhancement of radiation-induced cell kill by platinum complexes (carboplatin and iproplatin) in V79 cells.

Two second generation platinum complexes currently undergoing clinical chemotherapeutic trials, carboplatin (CBDCA) and iproplatin (CHIP), were evaluated for their ability to alter the survival of cultured Chinese hamster V79 cells following irradiation. Two protocols were employed. In the first, the drug was added to preplated cells, some of which were subsequently made hypoxic with nitrogen gas. These hypoxic cells were irradiated following 1 hour exposure to drug and survival was assessed by standard colony forming unit (CFU) methods. Enhancement ratios (ER) of approximately 1.4 were obtained for irradiation under hypoxic conditions, if the cells were exposed to equitoxic doses of CBDCA (500 microM) CHIP (50 microM). In the second series of experiments, cells were treated with 10 Gy in air and then incubated for various times prior to trypsinization and serial dilution of single cell suspensions. Six hours after irradiation, cells treated with X rays alone had recovered to produce a surviving fraction twice that of cells trypsinized immediately after irradiation (not held). Post-irradiation administration of CBDCA (50 microM) or CHIP (20 microM), at a time when free radical-mediated radiosensitization would not be possible, operationally inhibited this recovery from radiation-induced potentially lethal damage (PLD). Inhibition, expressed as recovery inhibition factor (RIF) after 6 hr with drug, was 2.0 for CBDCA and 1.2 for CHIP. These results suggest that the rationale for designing clinical trials to exploit interactions between cisplatin and radiation might also extend to include combined modality therapy using radiation with either of these two platinum complexes.

Irradiation enhances cellular uptake of carboplatin.

PURPOSE: Because radiation is known to damage cellular membranes, the purpose of this study was to determine whether irradiation of cultured cells might modify the cellular uptake of the chemotherapy agent carboplatin. METHODS AND MATERIALS: Total intracellular platinum was measured using atomic absorption spectrometry in cultured V79 cells and in four Chinese hamster ovary (CHO) cell lines. RESULTS: Intracellular carboplatin concentrations increased linearly with radiation dose (10-50 Gy) under both hypoxic and oxic irradiation conditions. Similar doses of radiation did not significantly increase the uptake of a nontoxic platinum compound [Pt(NH3)4Cl2.H2O] (p > 0.5). Compared to unirradiated controls, there was no increase in intracellular carboplatin concentrations when carboplatin was irradiated prior to administration to the cell cultures (p > 0.5). Within the 32.5 min or less required to deliver the radiation, a dose of 50 Gy produced approximately a 50% increase in intracellular platinum in V79 cells and approximately an increase of a factor of 1.3-1.6 in the CHO cell lines. Although the increase in drug uptake would be expected to be less than 10% for most cell lines at the doses of radiation used to investigate radiosensitization by carboplatin, this level of increase may play a significant role in the radioenhancement observed in UV41 cells because these excision-repair--deficient cells are much more sensitive to carboplatin as measured by cytotoxicity. CONCLUSION: These results suggest that some of the enhanced cell killing that results when cells are exposed to carboplatin in combination with radiation may be attributed to an increased cellular uptake. One mechanism of radiopotentiation may be an enhanced chemotoxicity resulting from a radiation-induced increase in carboplatin uptake.

Experimental brain hyperthermia: techniques for heat delivery and thermometry.

An experimental canine brain model was developed to assess the effects of hyperthermia for a range of time and temperature endpoints, delivered within a specified distance of an interstitial microwave antenna in normal brain. The target temperature location was defined radially at 5.0 or 7.5 mm from the microwave source at the longitudinal location of maximum heating along the antenna in the left cerebral cortex. Temperatures were measured with fiberoptic probes in a coronal plane at this location in an orthogonal catheter at 1.0 mm intervals. Six antennas were evaluated, including dipole, modified dipole, and four shorted helical antennas with coil lengths from 0.5 to 3.9 cm. Antenna performance evaluated in tissue equivalent phantom by adjusting frequency at a fixed insertion depth of 7.8 cm or adjusting insertion depth at 915 MHz showed dipoles to be much more sensitive to insertion depth and frequency change than helical antennas. Specific absorption rate (SAR) was measured in a brain/skull phantom and isoSAR contours were plotted. In vivo temperature studies were also used to evaluate antenna performance in large and small canine brain tissues. A helical antenna with a 2.0 cm coil length driven at 915 MHz was chosen for the beagle experiments because of tip heating characteristics, well-localized heating along the coil length, and heating pattern appropriate to the smaller beagle cranial vault. Verification of lesion dimensions in 3-D was obtained by orthogonal MRI scans and histology to document the desired heat effect, which was to obtain an imagable lesion with well-defined blood-brain-barrier breakdown and necrotic zones. The desired lesion size was between 1.5 to 2.5 cm diameter radially, in the coronal plane with the greatest diameter.

Combined modality treatment with ternary Cu(II) complexes and X rays.

Ternary Cu(II) complexes with bidentate malonato- and heterocyclic amine ligands were tested with regard to cytotoxicity and potentiation of x-ray induced cell killing in V79 cells. Two lead complexes were also tested in a tumor assay using the MTG-B murine adenocarcinoma model growing in the flanks of female C3H/HeJ mice. One complex, [2,2'-bipyridyl malonatoCu(II)] (RL-5077), produced sensitizer enhancement ratios (SER's) of 1.8 (hypoxic conditions) and 1.0 (oxic conditions) in vitro when irradiation followed 1 hr exposure to the drug at 100 microM. When RL-5077 was administered at doses of 1/2 (11.65 mg/kg) or 1/4 (5.25 mg/kg) the maximum tolerated dose (MTD), 15 min prior to a locally delivered dose of 20 Gy, enhancement ratios (ER's) of 1.6 and 2, respectively, resulted. The second lead complex, [1,10 phenanthroline (malonato)Cu(II)hydrate] (RL-5027), produced SER's of 1.8 and 1.2 under hypoxic and oxic conditions, respectively, at a concentration of 25 microM. Injection of RL-5027 (5 mg/kg) resulted in toxicity without enhancement in combination with radiation. Analogues of these two complexes have been synthesized in an effort to optimize the potentiation of radiation effects while minimizing toxicity to drug alone and increasing water solubility of the drug. Further studies of the structure-activity relationship of Cu(II) ternary complexes using in vitro radiosensitization as the endpoint have identified four classes of ligands with varying biological activity and have supplied information about the effects of group substitution on solubility, toxicity, and radiation potentiation. This group of complexes represents a new class of radiopotentiators that deserves further investigation into its potential for clinical use.

Potentiation of radiation-induced cell kill by synthetic metalloporphyrins.

The effects of the combination of several meso-substituted, water soluble metalloporphyrins with ionizing radiation on hypoxic and oxic monolayers of Chinese hamster fibroblast (V79N) cells were studied. The metalloporphyrins tested included a series of cationic metalloporphyrins complexed with Co(III), Zn(II), Fe(III), Cu(II), Pd(II) or Mn(III) and a series of anionic porphyrins chelated with Co(III), Fe(III), Cu(II), Rh(III), Mn(III) or Sn(IV). Both cationic and anionic free porphyrins were also tested. Cationic ligands were tetrakis(4N-methylpyridyl)porphine [TMPyP], tetrakis(4N-trimethylamino phenyl)porphine [TMAP], tetrakis(4N-butylpyridyl)porphine [TBPyP] and tetrakis(3N-methylpyridyl)porphine [3TMPyP]. Anionic ligands tested were tetrakis(4-sulfonato phenyl)porphine [TPPS], tetrakis(biphenyl)porphine sulfonate [TBPS] and tetrakis(4-carboxyphenyl)porphine [TCPP]. SER calculated from survival curves and SFR from one radiation dose were used to assess the relative effectiveness of this class as non-cytotoxic hypoxic and oxic cell-kill potentiators. Comparisons were made at 100 microM, which was essentially non-toxic (greater than 70% survival) for all porphyrins tested except for Co[TMPyP] (approximately 50% survival after 1 hour at 37 degrees C under oxic conditions). The greatest effects on radiation-induced cell kill were achieved with Co[TPPS] and Co[TMPyP] with SER values of 2.3 and 2.4 respectively. Porphyrin analogs with no coordinated metal were found to be less active than the same compound with metal. The overall charge on the molecule did not systematically relate to the biological activity of the compounds tested.

Intraoperative interstitial microwave-induced hyperthermia and brachytherapy.

Intra-operative placement of 11-gauge nylon catheters into deep-seated unresectable tumors for interstitial brachytherapy permits localized heating of tumors (hyperthermia) using microwave (915 MHz) antennas which are inserted into these catheters. Four preliminary cases are described where epithelial tumors at various sites were implanted with an antenna array and heated for 1 hour, both before and after the iridium-192 brachytherapy. Temperatures were monitored in catheters required for the appropriate radiation dosimetry but not required for the interstitial microwave antenna array hyperthermia (IMAAH) system. Additional thermometry was obtained using nonperturbed fiberoptic thermometry probes inserted into the catheters' housing antennas. No significant complications, such as bleeding or infection, were observed. This approach to cancer therapy is shown to be feasible and it produces controlled, localized hyperthermia, with temperatures of 50 degrees C or more in tumors. This technique may offer a therapeutic option for pelvic, intra-abdominal and head and neck tumors.

Effect of step-down heating on brachytherapy in a murine tumor system.

The effects of step-down heating combined with low-dose-rate irradiation (brachytherapy) were studied using a murine mammary adenocarcinoma (MTG-B) grown in the flanks of C3H mice. Treatment was initiated when tumors reached 0.9 to 1.1 cm in diameter. Step-down heating consisted of 7.5 min at 45 degrees C immediately followed by 7.5 min at 42 degrees C. Step-up heating consisted of 7.5 min at 42 degrees C immediately followed by 7.5 min at 45 degrees C. Step-down heating and step-up heating were compared to a single 45 degrees C, 15-min hyperthermia treatment. These hyperthermia protocols were combined before, in the middle of, or after brachytherapy. There were 4 untreated controls, 6 sham controls, and 11 treated animals in each of the brachytherapy-alone and combined treatment groups. The entire experiment was repeated at brachytherapy doses of 988, 1273, and 1603 cGy. In addition, the effects of step-down heating, step-up heating, and single-temperature hyperthermia were tested alone and in combination with sham treatment for each sequence. Based on daily measurements of tumor diameter, the growth delay to doubling volume was used as the biological end point. To compare the various treatment protocols, an isoeffect thermal enhancement ratio (TERiso) was calculated. Step-down heating after 988 cGy brachytherapy had a TERiso of 2.0 +/- 0.04, while step-up heating after 988 cGy brachytherapy had a TERiso of 1.7 +/- 0.05. Overall, the thermal enhancement ratios calculated from these growth delays indicate that step-down heating caused significantly greater hyperthermic radiosensitization than step-up heating when combined with brachytherapy.

Radioemetic protection at 24 h after 60Co irradiation in both normal and postremectomized cats.

The radioemetic dose-response relationships were established in 46 unanesthetized cats for each of two whole-body exposures, 24 h apart, to 60Co radiation at selected doses between 7.5 and 60 Gy. Individual episodes of vomiting were recorded for a period of 48 h as distinctive intrathoracic pressure deflections signaled through a catheter placed in the superior vena cava. Five cats with chronic lesions of the area postrema were included in the group exposed to 45 Gy. The lesioned animals were not detectably different in their radiation response behavior from the intact cats. Initial exposure in the entire cat series produced an increasing incidence of radioemesis from 25 to 80% over the specified dose range for the first observation period of 24 h. By contrast, the second exposure produced an inverse dose-related incidence of emesis varying from 63% to zero with an apparent crossover of radioemetic susceptibility for the two exposures at about 15 Gy. Complete protection during 12 h after the second exposure was obtained at 30, 45, and 60 Gy, and for all of 24 h at 45 and 60 Gy. In a separate group of 11 normal cats, the emetic drug xylazine invariably evoked vomiting when radioemetic protection was otherwise manifest after initial irradiation at 45 Gy. We conclude that the temporary recovery of well-being following acute lethal irradiation results selectively through increased radioemetic resistance, and it does not depend on the integrity of the area postrema.

Acute radiation-induced vomiting in area postrema-ablated cats.

A dose-response relationship was established in normal unanesthetized cats for emetic incidence, latency to onset of vomiting, and duration of emetic activity over a period of 24 h after whole-body exposure to 60Co radiation at selected doses between 7.5 and 90 Gy. Each episode of vomiting, i.e., retching and expulsion, was recorded oscillographically as its characteristic intrathoracic pressure waveform by means of a catheter inserted some days before into the superior vena cava. The gamma-radiation dose of 45 Gy evoked vomiting optimally with an incidence of 92% and an average onset time of 98 min. When administered to animals prepared chronically with surgical ablation of the area postrema, the same dose of radiation evoked vomiting in four of five test cases and with an average time to onset that was not by either measure significantly different from normal. Vomiting was also elicited in all of six normal cats exposed to an intestinal dose of 45 Gy X radiation with the head shielded. The same form of irradiation evoked vomiting in two of three chronically postremectomized cats. Successful ablation of the area postrema was determined functionally by emetic refractoriness to an injection of digitalis and confirmed for completeness by histological examination. It is concluded that the area postrema is not an essential element in the reflex mechanism of radiation-induced vomiting and, therefore, no physiological basis exists for dependence on a centrally acting chemogenic factor in radioemesis.

Toxic variability and radiation potentiation by Rh(III) complexes in Salmonella typhimurium cells.

Stationary-phase cells of Salmonella typhimurium were irradiated in phosphate-buffered saline in the presence of rhodium complexes to test for the potentiation of radiation-induced cell killing. Eleven Rh complexes, two Rh(I) and nine Rh(III), were tested. Seven Rh(III) complexes were found to be radiation potentiators; six potentiate only under hypoxic conditions, and one potentiates under both hypoxic and oxic conditions. Four of these seven Rh(III) complexes demonstrate potentiation that is 2 to 13 times greater than the sensitization caused by oxygen. Irradiating cells in Ham's F-12 culture medium rather than in phosphate-buffered saline eliminates this latter hypoxic radiation potentiation. None of the seven Rh(III) radiation potentiators are directly toxic to cells. However, four complexes were tested for hypoxic radiation-induced cytocidal toxicity, and three were found to be toxic after irradiation. The efficiency of this toxicity is not sufficient to account for the observed radiation potentiation. It is suggested that both reductive and oxidative free radical events are involved in the spectrum of Rh(III) potentiation observed.

Carboplatin enhances the production and persistence of radiation-induced DNA single-strand breaks.

Fluorometric analysis of DNA unwinding and alkaline elution were used to investigate the production and persistence of DNA single-strand breaks (SSBs) in Chinese hamster V79 and xrs-5 cells treated with the chemotherapeutic agent carboplatin in combination with radiation. Carboplatin was administered to cells before irradiation in hypoxic conditions, or the drug was added immediately after irradiation during the postirradiation recovery period in air. The results of DNA unwinding studies suggest that carboplatin enhances the production of radiation-induced SSBs in hypoxic V79 cells and xrs-5 cells by a factor of 1.86 and 1.83, respectively, when combined with radiation compared to the SSBs produced by irradiation alone. Carboplatin alone did not produce a measurable number of SSBs. Alkaline elution profiles also indicated that the rate of elution of SSBs was higher in cells treated with the carboplatin-radiation combination in hypoxia when compared to irradiation alone, resulting in an increased yield of radiation-induced SSBs by a factor of 1.46 in V79 cells with 20 Gy irradiation and by a factor of 2.02 in xrs-5 cells with 20 Gy irradiation. When carboplatin is present after irradiation and during the postirradiation recovery period, the rejoining of radiation-induced SSBs is inhibited during this postirradiation incubation period (radiopotentiation) with a relative inhibition factor at 1 h postirradiation of 1.25 in V79 cells and 1.15 in xrs-5 cells. An increased production and persistence of SSBs resulting from the interaction of carboplatin with radiation may be an important step in the mechanism responsible for the potentiated cell killing reported previously from studies in animal tumors and in cultured cells.

Production of DNA double-strand breaks by interactions between carboplatin and radiation: a potential mechanism for radiopotentiation.

The production of DNA double-strand breaks (DSBs) was studied in cells of four CHO cell lines under conditions where combining radiation with carboplatin enhanced cell killing (radiosensitization and radiopotentiation). The cell lines included repair-proficient (AA8 and K1), excision repair-deficient (UV41) and DSB repair-deficient (xrs-5) cells. Double-strand breaks were analyzed by neutral elution either immediately after or 4 h after a single 55-Gy radiation dose delivered under hypoxic conditions. Carboplatin (1 mM) combined with radiation produced a small increase in DSBs compared to radiation alone immediately after irradiation in AA8, UV41 and xrs-5 cells. However, the yield of DSBs in AA8, K1 and xrs-5 cells was significantly higher 4 h after carboplatin-radiation treatment; no such increase was found at 4h in UV41 cells. Strand scission factors (SSFs) were calculated as SSF = -log [percentage DNA remaining on filter at 8 h elution (treated cells)/percentage DNA remaining at 8 h elution (untreated cells)]. The ratios of the SSF at 4 h to 0 h postirradiation for carboplatin-treated cells were 13.7 for K1, 4.9 for xrs-5, 2.5 for AA8 and 1.2 for UV41 cells. These results support a possible explanation for the enhanced killing of irradiated cells by platinum chemotherapeutic agents, namely enhanced production of DSBs.

Toxic variability and radiation sensitization by Pt(II) analogs in Salmonella typhimurium cells.

A rationale is presented for the development of toxic, i.e., cytocidal, antitumor drugs as clinical hypoxic cell radiation sensitizers. Pt(II) complex-induced hypoxic cell radiation sensitization may occur from Pt(II) complex in free solution and Pt(II) bound to DNA. Although both the free solution and the bound compartments may operate, the free solution compartment is more likely amenable to experimental and clinical control in the case of systemically active Pt drugs. Assuming equivalent cell uptake of different Pt(II) complexes, the free solution compartment of Pt(II) sensitization can be increased by utilizing less toxic analogs of the antitumor drug cis-dichlorodiammineplatinum(II). One such less toxic Pt(II) sensitizer currently in clinical use is found to be cis-(1,1-cyclobutanedicarboxylato)diammineplatinum(II). A new finding of both clinical and mechanistic usefulness is described: irradiation of hypoxic solutions of four cis-Pt(II) complexes, but not two trans-Pt(II) complexes, creates products that cause toxicity in excess of the unirradiated solutions.

Response of a brachytherapy model using 125I in a murine tumor system.

The effects of low-dose-rate irradiation (brachytherapy) were investigated in vivo using a murine mammary adenocarcinoma (MTG-B) growing in the flank of C3H mice. For local tumor irradiations, a noninvasive cap was devised to cover the tumor and house three 125I seeds (average apparent activity 5.2 mCi each) located at 120 degree intervals around the circumference of the hemispherical cap (13 mm i.d.). Mice were secured during treatment in a tube allowing limited mobility while restricting access to the seeds. Tumors were exposed to a series of dose rates ranging from 14-40 cGy/h, and the total dose over the treatment interval (48 or 72 h) ranged from 830 to 2378 cGy. A total of nine experiments were conducted using the caps over a 10-week interval. In each experiment three groups (irradiated tumors, sham controls, and untreated controls) were analyzed, each containing 8-15 mice (N = 34, untreated control; N = 46, sham control; N = 91, brachytherapy irradiation). The brachytherapy results are compared to the effects of external beam irradiation in the same tumor system. A linear relationship was observed between the total radiation dose and doubling volume growth delay (GDDV) or treatment volume growth delay (GDTV) for the brachytherapy and external beam irradiation. The slopes of the dose-response curves are steeper for the acute dose (517 cGy/min) external beam irradiation (0.0072 day/cGy, GDDV; 0.00695 day/cGy, GDTV) than for the brachytherapy (0.0050 day/cGy, GDDV; 0.0057 day/cGy, GDTV) using both GDTV and GDDV end points. Comparison of the tumor volume regrowth slopes indicates that the tumor bed effect is larger for external beam irradiation than for brachytherapy, suggesting that the tumor bed effect may be dose-rate dependent.

Enhanced radiation-induced cell killing by carboplatin in cells of repair-proficient and repair-deficient cell lines.

The objective of this study was to determine whether a deficiency for either one of two repair processes influences the phenomenon of enhancement of radiation-induced cell killing by carboplatin which has been reported previously in one cell line (V79) and which is presumably a result of an interaction between these two therapeutic modalities. Cell killing was enhanced in cells of four cell lines when the cells were exposed to carboplatin before and during irradiation in either air or hypoxia. In cell lines proficient in both excision repair and DNA double-strand break repair (K1 and AA8), and in a cell line deficient in nucleotide excision repair (UV41), the enhancement was characterized as both a reduction in the shoulder region of the survival curves indicated by a reduced Dq and a reduction in D0 in the terminal region of the survival curves determined for cells exposed in air and under hypoxic conditions. Only the latter effect was observed in a cell line deficient in DNA double-strand break repair (xrs-5). The survival curves were fitted to the data using the repair saturation model and a computer program developed by N. Albright (Radiat. Res. 118, 112-130, 1989). In hypoxia, the reductions in Dq were as great as from 7.0 Gy to 2.1 Gy, 3.3 Gy to 0 Gy and 1.7 Gy to 0 Gy for K1, AA8 and UV41 cells, respectively. Sensitizer enhancement ratios ranged from 1.3 to 1.7 and were similar for irradiation in air and under hypoxic conditions. This enhanced cell killing by carboplatin combined with radiation required levels of the drug sufficient to produce cytotoxicity by the drug alone as exemplified by the UV41 cell line, which is intrinsically sensitive to carboplatin and in which 1/30 of the drug concentration required for the other cell lines produced an enhanced cell killing at an equitoxic dose of only 5 microM.