Contents
Targeted
Delivery of Therapeutics by Aerosol for Cancer of the Lung
Guest
Editor: Ajay Gautam
Aerosol Therapy for Malignancy Involving the
Lungs Pp.239-250
R.D.
Rao , S.N. Markovic and P.M. Anderson
Camptothecins and Lung Cancer: Improved
Delivery Systems by Aerosol
Pp.251-264
N.V.
Koshkina , J.C. Waldrep and V. Knight
Targeting the Lung: Preclinical and
Comparative Evaluation of Anticancer Aerosols in Dogs with Naturally Occurring
Cancers Pp.265-273
Chand
Khanna and David M. Vail
The Re-Emergence of Aerosol Gene Delivery: A
Viable Approach to Lung Cancer Therapy Pp.275-286
Charles
L. Densmore
Paclitaxel (Taxol) and Taxoid Derivates for
Lung Cancer Treatment: Potential for Aerosol Delivery Pp.287-296
Ajay Gautam and Nadezhda Koshkina
[Back to top] Aerosol Therapy for Malignancy Involving the Lungs
R.D. Rao , S.N. Markovic and P.M. Anderson
The lungs are
common sites of involvement by primary and metastatic malignant disease.
Patients with malignancies in the lung have limited treatment options and are
usually not curable. Numerous investigators have studied the potential of
delivering various therapeutic agents directly to the lungs and pulmonary
lymphatics by nebulization. Most of the research involves the use of
immunomodulatory strategies; a few aerosol studies of chemotherapy and gene
therapy have also been conducted. Most of these studies have been conducted in
animal models. A few human trials have also been completed. Results suggest
that aerosol therapies have the potential to shrink pulmonary metastases of
selected histologies, and that survival in selected patients with metastatic
renal cell cancer may be prolonged. The approach to therapy of cancer in the
lungs holds promise as a means to avoid systemic toxicity and obtain an
improved therapeutic effect. Research is currently underway to address issues
of local versus systemic toxicity, optimal drug delivery and selection of
optimal drugs and schedules including outpatient aerosol therapy. Future issues
in design of aerosol cancer treatment include identifying effective
combinations of agents, schedules, and use of aerosol therapy at home as
adjuvant therapy.
[Back to top] Camptothecins and Lung Cancer: Improved
Delivery Systems by Aerosol
N.V.
Koshkina , J.C. Waldrep and V. Knight
Lung cancer is the
largest and the most common cause of cancer-related deaths worldwide. The cure
rate for lung cancer remains lowest among all malignancies. The discovery of
new chemical agents with activity in first onset and recurrent disease is
crucial for advancing treatment of patients with pulmonary tumors. Camptothecins
are known as inhibitors of topoisomerase I, one of the key enzymes for DNA
replication and subsequent cell proliferation. Preclinical and clinical studies
had shown that the camptothecins are active against lung cancer and other solid
malignancies. In this paper, we review the status of camptothecin and
derivatives for treatment of pulmonary cancers, including the development of
new formulations and, particularly, novel aerosol routes of drug
administration, and their application in combination therapy.
[Back to top] Targeting the Lung: Preclinical and
Comparative Evaluation of Anticancer Aerosols in Dogs with Naturally Occurring
Cancers
Pet dogs with
naturally occurring cancers offer a novel opportunity for the study of both
cancer biology and therapy. The following review will provide the rationale for
the use of these spontaneous cancer models in translational research,
particularly in the development of anticancer aerosols. A summary of work
involving pet dogs with primary and metastatic cancers to the lung and the
investigation of therapeutic chemotherapy and cytokine immunotherapy aerosols
will be presented.
[Back to top] The Re-Emergence of Aerosol Gene Delivery: A
Viable Approach to Lung Cancer Therapy
Charles L. Densmore
The long-term
survival of lung cancer patients treated with conventional therapies (surgery,
radiation therapy and chemotherapy) remains poor and has changed little in decades.
The need for novel approaches remains high and gene therapy holds promise in
this area. A number of genes have been shown in vitro, in animal studies and
most recently, in human clinical trials, to have antitumor actions. However, a
number of problems still exist and success in human patients to date has been
marginal. Among the numerous considerations are the efficiency of delivery of
the gene to the tumor or, if an indirect effect is the aim, possibly nontumor
tissues, the efficiency and persistence of expression of the therapeutic gene,
the specificity of the gene action against the tumor, potential toxic or
pathogenic consequences of either the genes or the delivery vectors used,
convenience of the therapy and how likely the therapy will compliment or
complicate other conventional anticancer therapies. After the cloning of the
cystic fibrosis gene, there was great interest in the noninvasive delivery of
genes directly to the pulmonary surfaces by aerosol. Clearly, this approach
could have application to some pulmonary cancers as well and most early efforts
focused mainly on the use of nonviral vectors, primarily cationic lipids.
Unfortunately, nebulization shear forces and inefficient pulmonary uptake and
expression of plasmid DNA-cationic lipid formulations have generally resulted
in a lack of therapeutic effect, so much of this work has diminished in recent
years. Polyethyleneimine (PEI)-based formulations have proven stable during
nebulization and result in nearly 100% efficient transfection throughout the
airways and lung parenchyma. Therapeutic responses have been obtained in
several animal lung tumor models when PEIbased formulations of p53 and other
antitumor genes were delivered by aerosol. In addition, this mode of delivery
seems to be associated with low toxicity and results in little or none of the
immunostimulatory response typically associated with the delivery of
bacterially produced plasmid DNA containing unmethylated CpG motifs, which has
presented a challenge to repeated gene therapy via other modes of delivery.
Other potential applications of PEI aerosol gene delivery include the treatment
of asthma, lung alveolitis and fibrosis and a variety of monogeneic diseases
such as cystic fibrosis and alpha-1-antitrypsin deficiency. In addition, a wide
range of conditions treatable via genetic immunization could benefit from this
approach to gene delivery as well.
[Back to top] Paclitaxel (Taxol) and Taxoid Derivates for Lung Cancer Treatment:
Potential for Aerosol Delivery
Ajay
Gautam and Nadezhda Koshkina
Paclitaxel (PTX,
Taxol) has revolutionized cancer treatment in the past decade and is recognized
as one of the biggest advances in oncology medicine. In spite of the good
clinical efficacy shown by PTX, there is still a growing need to achieve better
safety and pharmacokinetic profile of PTX in patients. The standard delivery
modalities of intravenous infusion result in multiple side effects, and
targeting of the drug to specific areas within the body can result in better
efficacy and lower toxicity. Aerosol delivery of therapeutic agents has the
potential of localizing the drugs specifically to the lung tissue, with a
comparable or better pharmacokinetics as compared to intravenous, oral or
intraperitoneal delivery. Aerosol delivery of PTX has not been studied
extensively, however, it holds immense potential for improving the efficacy
against lung tumors. Early pre-clinical studies in mice and dogs have shown
good promise, both for pharmacokinetics of PTX, safety and efficacy in lung
cancer models. This review looks at the still developing approach of aerosol
delivery of PTX for lung cancer, documents the progress so far and the future
directions that can bring this approach to clinical reality.