Radiotherapy in the management of pancreatic islet cell tumors

Malignant islet cell tumors are commonly treated with surgical resection. Chemotherapy is reserved for residual, unresectable, or metastatic disease. The role for radiotherapy has not been clearly defined. This article describes three cases of advanced islet cell tumors treated effectively with radiotherapy. This experience, in addition to that from other published reports, suggests that radiotherapy is a useful mode for treating advanced islet cell carcinoma.     

Interstitial radiation therapy for hepatic metastases: sonographic guidance for applicator placement

A new technique is reported for the treatment of hepatic metastases using sonography-directed percutaneous placement of a 14-gauge needle applicator and a high-intensity "remote afterloading" iridium-192 (Ir-192) source for interstitial radiation therapy. The results with six patients show that the procedure is easily performed, patient tolerance is good, and there is minimal disruption of the patient's lifestyle. Hospitalizations have been less than 24 hr. Partial response or stable disease in the liver was observed in all six patients. Tumoricidal doses up to 5000 rad (cGy) in a single treatment with durations from 7 to 41 min were achieved in small volumes (less than 25 cm3) with no clinically significant toxicity on follow-up evaluations from 2-6 months. The technique appears to ablate discrete metastatic tumor deposits in the liver.     

Significant disparity in base and sugar damage in DNA resulting from neutron and electron irradiation

In this study, a comparison of the effects of neutron and electron irradiation of aqueous DNA solutions was investigated to characterize potential neutron signatures in DNA damage induction. Ionizing radiation generates numerous lesions in DNA, including base and sugar lesions, lesions involving base–sugar combinations (e.g. 8,5′-cyclopurine-2′-deoxynucleosides) and DNA–protein cross-links, as well as single- and double-strand breaks and clustered damage. The characteristics of damage depend on the linear energy transfer (LET) of the incident radiation. Here we investigated DNA damage using aqueous DNA solutions in 10 mmol/l phosphate buffer from 0–80 Gy by low-LET electrons (10 Gy/min) and the specific high-LET (∼0.16 Gy/h) neutrons formed by spontaneous ²⁵²Cf decay fissions. 8-hydroxy-2′-deoxyguanosine (8-OH-dG), (5′R)-8,5′-cyclo-2′-deoxyadenosine (R-cdA) and (5′S)-8,5′-cyclo-2′-deoxyadenosine (S-cdA) were quantified using liquid chromatography–isotope-dilution tandem mass spectrometry to demonstrate a linear dose dependence for induction of 8-OH-dG by both types of radiation, although neutron irradiation was ∼50% less effective at a given dose compared with electron irradiation. Electron irradiation resulted in an exponential increase in S-cdA and R-cdA with dose, whereas neutron irradiation induced substantially less damage and the amount of damage increased only gradually with dose. Addition of 30 mmol/l 2-amino-2-(hydroxymethyl)-1,3-propanediol (TRIS), a free radical scavenger, to the DNA solution before irradiation reduced lesion induction to background levels for both types of radiation. These results provide insight into the mechanisms of DNA damage by high-LET ²⁵²Cf decay neutrons and low-LET electrons, leading to enhanced understanding of the potential biological effects of these types of irradiation.     

Pharmacokinetics, toxicity, and efficacy of ends-modified raf antisense oligodeoxyribonucleotide encapsulated in a novel cationic liposome.

Raf-1 protein serine threonine kinase plays an important role in cell survival and proliferation. Antisense inhibition of Raf-1 expression has been shown to enhance the cytotoxic effects of radiation and anticancer drugs. Here we have evaluated the toxicity, pharmacokinetics, and antitumor efficacy of a novel formulation of liposome-entrapped raf antisense oligodeoxyribonucleotide (LErafAON). The LErafAON preparation showed high liposome entrapment efficiency of rafAON (>85%) and stability at room temperature. In CD2F1 mice, administration of LErafAON produced no morbidity/mortality (5-35 mg/kg/dose, i.v., x12). Dose-related elevations in liver enzymes (alanine aminotransferase and aspartate aminotransferase) and histopathological changes in liver were noted in LErafAON and blank liposome groups. No morbidity/mortality and changes in clinical chemistry or histopathology were observed in New Zealand white rabbits (3.75 mg/kg/dose, i.v., x8; 6.5 mg/kg/dose, i.v., x6) or in cynomolgous monkeys (3.75 or 6.25 mg/kg/dose, i.v., x9). Transient decrease in total hemolytic complement activity (approximately 62-74%) and increases in C3a (approximately 3-fold) and Bb levels (approximately 5-12-fold) were observed in LErafAON and blank liposome groups of monkeys. A 30 mg/kg i.v. dose of LErafAON in human prostate tumor (PC-3)-bearing BALB/c athymic mice gave a terminal plasma half-life of 27 h, and intact rafAON could be detected in plasma and in normal and tumor tissues for up to at least 48 h. In monkeys, the terminal plasma half-life of 30.36 +/- 23.87 h was observed at an i.v. dose of 6.25 mg/kg. LErafAON (25 mg/kg/dose, i.v., x10) or ionizing radiation (3.8 Gy/day, x5) treatment of PC-3 tumor-bearing athymic mice led to tumor growth arrest, whereas a combination of LErafAON and ionizing radiation treatments resulted in tumor regression. LErafAON treatment caused inhibition of Raf-1 protein expression in normal and tumor tissues in these mice (>50%, versus controls). These data have formed a basis of the clinical Phase I studies of LErafAON for cancer treatment.     

Enhanced therapeutic effects of doxorubicin and paclitaxel in combination with liposome-entrapped ends-modified raf antisense oligonucleotide against human prostate, lung and breast tumor models

Raf-1 protein kinase plays an important role in cell growth, proliferation and cell survival. We have previously described the use of liposome-entrapped antisense raf oligonucleotide (LErafAON) to inhibit Raf-1 expression resulting in tumor growth inhibition and radiosensitization. The present study was undertaken to evaluate the chemosensitization effects of LErafAON in combination with doxorubicin or paclitaxel on a panel of human tumor xenografts. LErafAON (25.0 mg/kg i.v. x 10) displayed significant antitumor activity (P<0.05) when administered as a single agent in prostate (PC-3), lung (A549) and breast (MDA-MB 231) carcinoma models. Doxorubicin (1.0-4.0 mg/kg i.v. per week x 3) and paclitaxel (1.0-4.0 mg/kg i.v. on alternate days x 3) were administered as single agents at non-toxic doses that led to only minimal to moderate antitumor activity. However, a combination of LErafAON with doxorubicin or paclitaxel led to significantly enhanced antitumor activity in all the tumor types tested (PC-3, P<0.03; A549, P<0.035; MDA-MB 231, P<0.045) as compared with LErafAON alone or chemotherapeutic agents alone treated groups. This effect of chemosensitization appeared to be sequence-specific because a mismatch control oligonucleotide continued to show significant tumor growth. Additionally, no inhibition in Raf-1 expression in MDA-MB 231 tumor tissue was observed with mismatch oligonucleotide treatment. On the other hand, LErafAON treatment led to >75% inhibition of Raf-1 expression in tumor tissue. These preclinical observations support the use of LErafAON in combination with chemotherapeutic agents to improve the treatment of human cancers.     

Enhanced radiation late effects and cellular radiation sensitivity in an ATM heterozygous breast cancer patient.

We observed severe late effects in a patient treated with radiation therapy for breast cancer. Radiation survival studies of patient fibroblasts show an enhanced cellular radiation sensitivity (Do = 0.95 Gy). Genetic analysis reveals that the patient is heterozygous for a mutated ATM gene. Protein truncation test (PTT) and sequence analysis identified a truncation within the leucine zipper domain, corresponding to a fragment previously reported to exhibit dominant negative function. These findings demonstrate that ATM heterozygosity may be associated with enhanced clinical radiation sensitivity and suggest a clinical relevance to this truncation that results in a dominant negative-acting protein.     

A randomized study of the efficacy of adjuvant local graft irradiation following renal transplantation

A prospective randomized study investigating the effectiveness of adjuvant local graft irradiation (LGI) following renal transplantation was performed at Georgetown University Hospital from 1983 until 1988. One hundred and thirty-eight patients were enrolled in the study with 117 patients receiving cadaver kidney transplantations and 21 patients receiving living related kidney transplantations. Seventy-one patients were randomized to receive adjuvant local graft irradiation consisting of 600 cGy in four fractions with chemical immunosuppression whereas the remaining 67 patients received chemical immunosuppression only (control group). The two groups were comparable at entry with respect to potentially important prognostic variables. Median follow-up for all patients was 30 months. The 3-year actuarial allograft success rate was 75% and 68% for the local graft irradiation and control groups, respectively. A nonsignificant trend favoring the irradiated group was noted. Subgroup analysis of the 21 recipients of kidneys from living related donors suggested an improvement in allograft survival for the local graft irradiation arm. Cadaver allograft survival was not significantly different between the two treatment arms. There was no apparent benefit in kidney function or time to the first rejection episode in the group receiving local graft irradiation.     

Relationship between DNA strand breaks and inhibition of poly(ADP-ribosylation): enhancement of carcinogen-induced transformation

Inhibition of poly(ADP-Rib) by benzamide (BA) or 3-aminobenzamide(3AB) for a limited period (i.e., when ADP-ribosylation is elevated)during and shortly following X-ray or MNNG-induced DNA damageof BALB/3T3 cells significantly (3- to 30-fold) enhanced transformationfrequency by these agents. Individual Type III foci isolatedfrom benzamide, X-ray, or X-ray plus benzamide treated cultureswere established and characterized for growth in soft agar andfor tumor induction in nude mice. DNA isolated from representativetransformed lines established as a result of BA, X-ray or X-rayand BA treatments was transfected onto NIH/3T3 cells. Transformationefficiencies ranging from 0.17 to 0.28 foci/ µg of DNAwere observed suggesting the possibility that dominant transforminggene(s) were responsible for the oncogenic phenotype of radiationand benzamide transformed DNA.