Tobacco chemicals:  Over 30 chemicals identified in cigarette smoke had been shown to be carcinogenic.  In the gas phase, several carcinogenic/tumor-promoting chemicals have been identified; these include dimethyl nitrosamine, vinyl chloride, acrolein, benzene, and dialkylnitrosoamines.  In the particulate phase carcinogenic and co-carcinogenic polyaromatic hydrocarbons (PAHs) have been identified as well as other agents including: methylated PAHs, heterocyclic hydrocarbons, chlorinated hydrocarbons, phenols, catechols as well as metals.  Agents found in tobacco smoke that are associated with pancreatic cancer and esophageal cancer include  N-nitrosamines and their precursors; aromatic amines which predispose to kidney and bladder cancer are also present.³ 

Chemotherapy drug treatment and late adverse consequences:

• Many antineoplastic drugs produce generalized cytotoxic effects and the drugs themselves may be carcinogenic. One category of chemotherapy agent, the alkylating drugs, has been associated with later, secondary tumor development. Acute myeloid leukemias is an example of a long-term consequence of Hodgkin's disease chemotherapy. This risk seems particularly associated with the alkylating chemotherapy drugs including cyclophosphamide, melphalan, busulfan, treosulfan, and semustine and with chemotherapy protocols that include alkylating agents.³  

Chemotherapy Alkylating Agent Examples

Cyclophosphamide	Semustine

• Two clinical syndromes, which may be fatal, are related to chemotherapy treatment: acute myeloid leukemia (AML) and myelodysplasia. Myelodysplasia may be observed in patients treated with alkylating drugs over a long period of time. In this setting the lifetime risk is approximately 2%, although the risk is higher if radiation treatment was associated with the therapy. The most likely period for this serious adverse effect is about 4-6 years following treatment. Acute myeloid leukemia can occur following patient treatment with topoisomerase-II inhibitors including etoposide and doxorubicin. This variant of AML exhibits a specific, characteristic chromosome translocation involving 10q23. The incidence for this consequence is <1%, typically occurring from about 1.5-3 years following treatment. These types of secondary or late-developing cancers (myelodysplasia and acute myeloid leukemia) tend to be resistant to treatment or prevention.⁴  

• Another example of a drug which is used to treat cancer but can also induce cancer is tamoxifen, which can cause endometrial cancer with a frequency of about 1%-2% in women taking the drug for five years or more. Typically the endometrial tumors are found early and ultimate mortality from endometrial cancer is every low compared to benefits attributable to tamoxifen in breast cancer management. ⁴  

• Other adverse effects following chemotherapy:⁴  

  • Glucocorticoid administration can affect bone adversely, causing avascular necrosis and osteoporosis. Glucocorticoid administration may also cause cataract formation.

  • Cytarabine (ara-C) and methotrexate may adversely affect brain function, inducing neuropsychiatric deficits.

  • Platinum, vincristine, and taxanes (e.g. Taxol) administration can result in peripheral nerve neuropathy including hearing loss.

  • Anthracyclines (anthracycline antibiotics) as well as trastuzumab administration is causative of cardiotoxicity, i.e. cardiomyopathy.

  • Bleomycin administration can cause pulmonary fibrosis; whereas, methotrexate administration may be associated with pulmonary hypersensitivity.

  • Reduced renal function and hypomagnesemia can occur following platinum administration (other agents can also cause these effects).

  • Alkylating agents can be associated with gonadal-effects, including infertility.

  • Many chemotherapy drugs exhibit toxic effects on bone marrow with clinical presentations including myelodysplasia, secondary leukemia, and aplasia.

Biomarkers represent potential end points for various assessments about, in this example cancer, including host susceptibility, underlying disease mechanisms, including molecular pathogenesis and carcinogen exposure assessment.   Biomarkers could include internal dose markers, biologically effective doses, early biologic effects, susceptibility, and disease.  More mechanistically oriented biomarkers might include determination of the extent of DNA adduct formation (molecular alteration in DNA by the carcinogen or its metabolic products), gene polymorphisms (a variation in DNA not associated with mutation, but rather a naturally occurring variant with a frequency of at least 1% in the overall population), cytogenetic changes, and mutations associated with cancer cells.  One example of a biomarker is insulinlike growth factor 1 (IGF-I) and related proteins.

• Central to the carcinogenic process is dysregulation of cell growth, leading to uncontrolled proliferation.  Insulin-like growth factors (IGF), IGF binding proteins (IGFBPs), particularly IGFBP3, as well as insulin are important in cell growth initiation and proliferation in, for example, colorectal cancer.  Insulin can be categorized as a metabolic signal; however, IGF-I is an important mitogenic and cell differentiation factor [a mitogen is a substance which promotes mitosis in eukaryotic, e.g. mammalian, cells]. Additionally, the insulin receptor substrate (IRS) protein family contains several members some of which, for example IRS-1 and IRS-2, are found in nearly all cells and tissues.  In tumors, IRS-1 may be a biomarker of an active IGF signal transduction path, although IRS is principally involved in insulin signaling.  Normally, IRS-1 regulates body growth and peripheral insulin activity, whereas, IRS-2 is a regulator for body weight control and glucose homeostasis.¹

• Regulation of insulin and IGFs depend on numerous factors such as diet, hormonal and genetic influences, and lifestyle.  In addition, IGF, IGFBP3, and IRS may also be affected by gene polymorphism.  An example of a gene polymorphism for IRS-1 is the G927R polymorphism that seems associated with insulin resistance and type 2 diabetes.   A hypothesis  related to this idea is that the IRS-1 R allele might increase colon cancer risk.  As another example IRS-2 G1057D polymorphism may, under certain circumstances related to body size, be also associated with insulin resistance. High IGF-I combined with low IGFBP3 serum levels have been reported in some investigations to be associated with colon cancer risk. Probably polymorphisms in IRS-1 and IRS-2 may have slight, independent influences on colon cancer risk; however, when IRS-1, IRS-2, IGF-I, and IGFBP3 factors are considered together, the cumulative influences on colon cancer risk appear more significant.  Possibly, the etiology of colon cancer may involve aberrations in insulin  pathways.¹

• Other studies have associated high serum insulin-like growth I (IGF-I) with increased risks of other cancers in addition to colorectal disease.  These other cancers include prostate, breast, and lung.  There is also a possible association between low circulating IGF-I serum levels and osteoporosis, impaired cognitive performance, and cardiac disease.²