Specific induction of tumor neovasculature death by modified murine PPE-1 promoter armed with HSV-TK.

BACKGROUND: One strategy to increase tissue specificity of gene therapy is to use promoters or enhancers. OBJECTIVES: (1) To enhance the selectivity of a murine preproendothelin-1 (PPE-1) promoter in tumor angiogenesis by using a positive endothelial transcription-binding element. (2) To test the specificity and efficiency of the modified PPE-1 promoter [PPE-1(3X)] in vitro and in vivo by using reporter genes, and the therapeutic gene herpes simplex virus-thymidine kinase (HSV-TK) in a mouse model of Lewis lung carcinoma (LLC). RESULTS: The modified PPE-1 promoter specifically induced expression in the tumor angiogenic vascular bed with a 35-fold higher expression compared to the normal vasculare bed of the lung. Thus, when the HSV-TK gene controlled by the modified PPE-1 promoter was used systemically, it induced tumor-specific necrosis, apoptosis and mononuclear infiltrates, leading to massive destruction of the neovasculature of the pulmonary metastasis, which suppressed metastasis development. CONCLUSIONS: These results show that an adenoviral vector armed with HSV-TK controlled by the endothelial-selective murine PPE-1(3X) promoter is efficient and safe to target tumor neovasculature.

Effect of otic medications containing glucocorticoids on liver function test results in healthy dogs.

Otic medications containing triamcinolone or dexamethasone were administered twice daily for 21 days to 2 groups of 4 healthy dogs each. Serum alkaline phosphatase, gamma-glutamyltransferase, alanine transaminase, and aspartate transaminase activities, and serum bile acid and lipoprotein-X concentrations were assayed for 35 days. Increased serum activities for gamma-glutamyltransferase, alkaline phosphatase, and alanine transaminase were detected by day 7 and peaked at day 21. Increases were greater in dogs given the dexamethasone-containing medication. Enzyme activity returned to baseline by day 35. Serum aspartate transaminase activity and bile acid and lipoprotein-X concentrations did not increase.

Adrenocortical suppression associated with topical otic administration of glucocorticoids in dogs.

Commercial otic preparations that contained dexamethasone or triamcinolone acetate were applied twice daily to both ears of 2 groups of dogs (n = 8). Marked adrenocortical suppression, reflected by low serum cortisol concentrations, was observed in all dogs. Results of ACTH response tests were blunted after 7 days of treatment. Twenty-one days after treatment, serum cortisol concentrations still were suppressed in all dogs, compared with pretreatment control concentrations. Fourteen days after cessation of otic treatment, 5 of 8 dogs still had inadequate release of cortisol in response to ACTH.

Biochemical evaluation of patients with breast cancer.

Peripheral blood specimens were obtained from 50 patients with various stages of breast cancer (I-II = 7, III = 6, IV = 24, treated and NED = 13), and 20 biochemical tests were performed. There are significant differences of hemoglobin, LDH, SGPT, serum protein, albumin, and alpha globulin values between patients with early (I, II, NED) and late (III, IV) lesions. Among patients with stage IV diseases, those patients with bony metastases had significantly higher values of alkaline phosphatase, alpha-1 globulin, IgA, and C-reactive protein than those with nonosseous lesions. Neither CEA nor pregnancy-associated alpha-2 glycoprotein showed any correlation with different stages or sites of breast cancer in these small series of patients.

Photochemistry: role of lasers.

This Technology editorial originally appeared in the Business Section of The New York Times, 21 May edition. It is reprinted here by permission.

Persistent carcinoma of the oropharynx and oral cavity re-treated by after-loading interstitial 192Ir implant.

After-loading implantation techniques apparently offer an effective alternative in the management of persistent (or recurrent) oropharynx and oral cavity carcinoma postirradiation. A total of 29 patients with such lesions was treated from February 1974, to July 1975, in the LAC/USC Radiation Medicine Section, using after-loading 192Ir implantation techniques. These patients all had extensive persistent cancer after "full tolerance" irradiation (with or without previous surgery) and were referred for palliation or for possible salvage. Additional doses administered ranged from 5000 to 7000 rads in three to five days. Eighteen of the 29 patients (63%) have had complete local control for 18 to 36 months. These patients have maintained a relatively satisfactory palliative status. Ten of the 29 are dead. Follow-up periods are short, but early indications are that problem patients with persistent cancer after "full tolerance irradiation" can be salvaged, or at least satisfactorily palliated, with after-loading interstitial implant techniques. Clinical details, sites of involvement, implantation techniques, dosimetry methodology, reactions and complications will be described.

Afterloading interstitial implant in the treatment of oral cavity and oropharyngeal cancers.

(1) In all, 70 patients with carcinoma of the oral cavity and oropharynx have been treated utilizing one or more of several interstitial iridium-192 afterloading techniques. (2) After an 18-month minimum follow-up period, local control is still maintained in 9 of 10 patients with T1 and T2 lesions (UICC), in 17 of 22 patients with T3 lesions, and in 21 of 38 patients reirradiated for recurrent disease. The complication rate of 29% in the reirradiated patients, though high, is considered acceptable in these essentially hopeless cases. (3) This preliminary report is made to stimulate interest in the role of interstitial iridium-192 afterloading techniques. We feel they deserve evaluation in a controlled study of other head and neck cancer management techniques (including external irradiation, surgical resection and adjunctive chemotherapy).

Technique of after-loading interstitial implants.

Interstitial implants are either removable or permanent (and occasionally a combination of both). Permanent implants are generally utilized where tumors are not accessible enough to permit easy removal of sources or where accurate source distribution is less critical. They are useful for cancers of the lung, pancreas, prostate, bladder, lymph nodes, etc. Radon and gold-198 have been largely replaced by iodine-125. Our major interests are in the removable after-loading iridium-192 implant techniques. Template (steel guide) and non-template (plastic tube) techniques are utilized. Templates are preferred where the tumor volume can only be approached from one side and where accurate positioning of sources would otherwise be difficult. They are useful for cancers of the cervix, vagina, urethra, and rectum. Non-template (plastic tube) techniques are preferred where the tumor volume can be approached from at least two sides and where templates are either not feasible or not essential for accurate positioning of sources. The single needle non-template approach is useful for cancers of lip, nodes, and breast (plastic button) and for cancers of the oral cavity and oropharynx (gold button). The paired needle non-template approach is useful for cancers of the gum, retromolar trigone, and base of tongue (loop technique) and for cancers of the palate (arch technique). Procedures for each technique are described in detail.