Growth inhibition of established B16-F10 lung metastases by sequential aerosol delivery of p53 gene and 9-nitrocamptothecin

Abstract

Growth inhibition of established tumor metastases in the lungs poses a difficult challenge for most clinical settings inLung cancer is the single largest cause of cancer deaths, with less than 15% of newly diagnosed patients surviving beyond 5 years. More than 80% of lung cancers do not respond favorably to chemotherapy. One of the primary clinical challenges is to overcome the tumor resistance to chemotherapeutic drugs. P53 tumor suppressor gene mutations are reported in a majority of lung cancers and loss of p53 function results in increased drug resistance and tumor relapse. 1 An approach postulated in recent years is p53 gene replacement into the tumor cells, which can then lead the cell into apoptosis as well as increase the sensitivity of the cells to chemotherapeutic drugs. 2,3 Most anti-cancer drugs have been conventionally delivered via oral or intravenous routes. Biodistribution of the drugs through these delivery strategies is widespread, with the ratio of the drug deposited in the lungs being low. 4 A similar distribution of transgene expression in various tissues is observed after intravenous or intraperi- toneal delivery of vector-DNA complexes for gene therapy. 5 Another concern is the systemic toxicity observed after oral or intravenous routes of delivery. Aerosol delivery of genes and chemotherapeutic drugs represents a very promising technology to target the lungs specifically, increasing the pulmonary deposition and pharmacokinetic profile of the drugs and genes. 4,6 We have previously demonstrated that polyethylenimine (PEI) can achieve high levels of transgene expression in the lungs after aerosol delivery, 6 with minimal toxicity or cytokine responses, 6,7 and the dose delivered by aerosol has been shown to result in an anti-tumor effect in two different lung cancer models, using the p53 tumor suppressor gene. 8,9 Also, we previously reported that aerosol delivery of a liposomal formulation of 9NC, a topoisomerase I inhibitor, can inhibit the growth of subcutaneous tumors as well as lung metastases. 10,11 In this report, we demonstrate that sequential delivery of p53 and 9NC by aerosol can arrest the growth of established B16-F10 melanoma pulmonary metastases in experimental mice.In order to study the combined effect of 9NC and p53 in vitro, B16-F10 cells grown in tissue culture plates were transfected with PEI-p53 or PEI-Neobam complexes (1

Nitric oxide regulates angiogenesis through a functional switch involving thrombospondin-1

“…The enhanced levels of p53-Ser-15P exhibited at 1-100 M DETA͞NO may be associated with the modest reaccumulation of TSP1 occurring at the same doses ( Fig. 2 A and B), which is consistent with the known positive regulation of TSP1 by P53 (23,(29)(30)(31). Steady-state nanomolar levels of NO associated with dose-response concentrations of DETA͞NO were determined by using a NO analyzer and compared with a standard curve generated by the reduction of NO 2 Ϫ and are shown in Fig.…”

Inhibition of metastatic lung cancer in C57BL/6 mice by liposome encapsulated all trans retinoic acid (ATRA)

“…The lung tumor was graded based on a scale of 1-5: b10 tumor foci -Grade 1; 10-100 foci -Grade 2; one lobe of lung is full of tumors -Grade 3; both lobes are full of tumors -Grade 4; and, if lungs are full of tumors and tumors were growing into chest wall -Grade 5 [35,36].…”

Evaluation of nose-only aerosol inhalation chamber and comparison of experimental results with mathematical simulation of aerosol deposition in mouse lungs

“…19 A murine metastatic lung carcinoma model was used to demonstrate the anticancer effects of aerosol delivery of tumor suppressor gene p-53 along with liposomal 9-campothecin delivered to the lung as an aerosol. 20 Experiments involving aerosol delivery in mice models of human diseases are expected to grow continuously.…”