Post by Max on Sept 21, 2005 14:09:20 GMT -5
Introduction
A recently published study has identified a doubled risk of cancer reoccurence in a large population with testicular cancer exposed to distinct cancer-treatments due to effects from the exposure. Statistically significantly increased risks of solid cancers were observed among patients treated with radiotherapy alone (RR = 2.0, 95% CI = 1.9 to 2.2), chemotherapy alone (RR = 1.8, 95% CI = 1.3 to 2.5), and both (RR = 2.9, 95% CI = 1.9 to 4.2) [1]. As of today, no study has evaluated the effects on cancer-susceptibility in subjects exposed to (Ro)accutane with no previous history of cancer. Hoffman la Roche itself, the distributor of (Ro)accutane sees no increased susceptibility for any type of cancer in (Ro)accutane exposed human subjects, but states that "new information may be available" [0].
At the moment, there is no direct evidence that would point out a drastically increased cancer-susceptibility in humans, however, the issue needs proper evaluation, since some studies are showing a direct connection between certain factors recognizable as results from (Ro)accutane exposure, such as vitamin D deficiency, with higher susceptibility for cancer. However, cancer susceptibility is a complex parameter, dependent on multiple variables as prognostic factors, often in combinations, and also different depending on type of cancer.
The effects regarding risks of cancer susceptibility later in life in (Ro)accutane exposed acne-subjects, with no previous history of cancer, are not known either at an empirical or a theoretical level. Various altered parameters in exposed subjects are pointing in opposite directions. This section is aimed at discussing how a (Ro)accutane exposure in acne-subjects may affect cancer susceptibility based on a set of known and discussed risk factors.
Generally can be said, that with the knowledge of today, the major parameters that talks against a higher susceptibility for certain cancers are certain hormonal deficiencys detected post (Ro)accutane exposure in human subjects, including androgen deficiency and thyroid deficiency. However, those parameters do not provide a fully intact result.
The paramaters talking for a higher cancer susceptibility can be described as the alterations in immune-function discovered in human subjects exposed to (Ro)accutane, including altered cytokine production, possibly altered macrophage activation and receptor malfunctions.
Vitamin A deficiency associated with higher incidence of cancer in experimental animals
Vitamin A deficiency in experimental animals has been associated with a higher incidence of cancer and with increased susceptibility to chemical carcinogens. This is in agreement with the epidemiological studies indicating that individuals with a lower dietary vitamin A intake are at a higher risk to develop cancer [2, 6 and more].
Loss of retinoid signaling and retinoid resistance due to lessened retinoid receptor function suggested to increase cancer susceptibility
Collections of data suggest that the RAR receptor acts as a tumour suppressor in several types of cancer, and confirm the role of retinoid signaling as important in cancer resistance [8 and more]. Tumour antigens such as PRAME may repress the retinoid receptor signaling and thus contribute to cancer development [10].
Exposure to retinoids in several types of cancer frequently lead to retinoid resistance and thus reoccurrence [9 and more]. These observations of retinoid resistance after heavy retinoid exposure may depend on a downregulation of retinoid receptor expression and coactivator function when supraphysiological doses of retinoids are administered to human subjects over time. After (Ro)accutane exposure in human acne-subjects, the expression of retinoid receptors, such as RAR receptors is surprisingly not either statistically or experimentally measured, but is likely to be significantly decreased. "In situ hybridization was used to compare retinoid receptor expression profiles in head and neck squamous cell carcinomas, dysplastic lesions, adjacent normal tissues, and in tissues from normal volunteers (Xu et al., 1994). RAR, RAR, and RAR and RXR and RXR mRNAs were expressed in all samples from normal volunteers. The levels of RAR and RAR and RXR and RXR mRNAs were similar to that in most of the adjacent normal, hyperplastic, dysplastic, and malignant tissues. However, RAR mRNA levels were detected in only 70% of dysplastic and adjacent normal tissues, and were repressed further in dysplastic and malignant epithelium. RAR repression was also found in preneoplastic oral cavity lesions (Lotan et al., 1995), non-small-cell lung cancer (Castillo et al., 1997; Xu et al., 1997a; Picard et al., 1999), breast cancers (Widschwendter et al., 1997; Xu et al., 1997b), and esophageal cancer (Qiu et al., 1999). Other retinoid receptors were expressed in these tissues, but only RAR levels were significantly lower in the premalignant and tumor tissues. The correlation of RAR repression with epithelial carcinogenesis led to the hypothesis that RAR could act as a tumor suppressor. This view was supported by experiments where RAR was overexpressed in cell lines. In retinoid-sensitive human lung carcinoma cells, constitutive overexpression of RAR2 inhibited cellular proliferation (Houle et al., 1993)" [8].
1. Possible increased risk for skin cancer, ultraviolet radiation induced tumours in subjects exposed to (Ro)accutane
Immunosuppressed patients are extremely susceptible to cutaneous squamous cell carcinoma, suggesting that immunosurveillance by T lymphocytes protects against this ultraviolet radiation-induced tumour. Both anti-CD8 and anti-CD4 treatment significantly enhanced the growth of transplanted tumours. In CD8-depleted animals, tumours grew rapidly in all animals. Tumour growth in CD4-depleted animals was slower, and 50% of these mice eventually rejected their tumours [3]. In transgenic mice local interruption of PML and RARalpha signaling in the skin, together with a systemic retinoid deficiency, initiates a tumor induction pathway that is independent of ras activation [4]. The major reason propounded for an association of sun exposure with a protective effect in the development of cancer and improved survival is that vitamin D synthesis is a critical component of cellular networks that inhibit cellular proliferation and encourage apoptosis [14].
2. Possible attenuated effects on lung cancer from outdoor airborne particulate matter (APM) and smoking in subjects exposed to (Ro)accutane
Findings of vitamin A status and possible attenuated effects from outdoor airborna particulate matter and smoking are pointing in different directions. The finnish ATBC study, involving a large population found that supplementation with supraphysiological doses of beta-carotene may modestly increase lung cancer incidence in cigarette smokers, and this effect may be associated with heavier smoking and higher alcohol intake [5].
However, the opposite, a pronounced vitamin A deficiency may be attenuated by APM. APM has the potency to deplete lung vitamin A in vivo and vitamin A might have a protective effect in the process of lung carcinogenesis, APM might increase the susceptibility for the development of lung cancer [6].
In mice, it was found that the the angiotensin II (AT2) receptor function in lung stromal fibroblasts may be a potential modulator of tumor susceptibility in chemical carcinogen-induced lung tumorigenesis. AT2 receptor null mice displayed higher susceptibility to lung cancer. The level of active TGF-beta in the conditioned medium was consistently higher with AT2-null fibroblasts than with wild-type fibroblasts [7]. The AT2 receptor is one of the receptors heavily affected from (Ro)accutane exposure, and its expression is suggested to be inhibited [8].
3. The metabolic syndrome, diabetes and cancer susceptibility
4. (Ro)accutane induced vitamin D deficiency and cancer susceptibility: suggested variations between type of cancer
A significant fall in the level of 1,25-dihydroxyvitamin D, and a significant increase in the molar ratio of 24, 25-dihydroxyvitamin D to 25-hydroxyvitamin D was found in human subjects after exposure to (Ro)accutane, indicating a (Ro)accutane induced significant 1,25-dihydroxyvitamin D deficiency [11].
Colon cancer and vitamin D deficiency
The relationship between vitamin D deficiency and colon cancer has been extensively shown [13, 15 and more]. In vitro and in vivo studies demonstrated that 1,25-dihydroxycholecalciferol [1,25(OH)(2)D(3)] and its analogs inhibit colon cancer cell proliferation. Vitamin D deficiency enhances the growth of colon cancer in mice. The tumor expression of VDR and 1alpha-OHase indicates possible autocrine/paracrine cell growth regulation by vitamin D [13].
Prostate cancer and vitamin D deficiency
Epidemiological evidence suggests that vitamin D deficiency also is associated with increased risk for prostate cancer. Results show that cholecalciferol, at physiological levels: (i) inhibits anchorage-dependent growth (ii) induces differentiation by increasing PSA expression and (iii) exerts its effects by up-regulating vitamin D receptor (VDR), retinoid-X receptors (RXRs), and androgen receptor (AR). Furthermore, it was discovered that human prostate epithelial cells constitutively express appreciable levels of 25-hydroxylase CYP27A1 protein, the enzyme which catalyzes the conversion of cholecalciferol to 25(OH)D(3), and that CYP27A1 is up-regulated by cholecalciferol. Recent studies show that human mitochondrial CYP27A1 can also catalyze 1alpha-hydroxylation of 25(OH)D(3) to calcitriol. The presence of 25-hydroxylase in human prostate epithelial cells has not previously been shown. Since human prostate epithelial cells have the necessary enzymes and the rare ability to locally convert cholecalciferol to the active hormone calcitriol, it is proposed that they are a prime target for chemoprevention of prostate cancer with cholecalciferol whose safety is well established as a supplement in vitamins and fortified foods [17].
1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) and its analogues have been shown to inhibit proliferation of human cancer cells mediated by vitamin D receptor (VDR). CYP24A1 mRNA was significantly up-regulated in colon, ovary and lung tumors, but down-regulated in breast tumor relative to the analogous normal tissues. As a comparison, VDR mRNA was modestly down-regulated in colon, breast and lung tumors, but highly up-regulated in ovarian tumors [12].
Hepatocarcinogenesis and vitamin D deficiency
In rats, labeling of oval cells, a cell compartment possibly associated with the repopulation of the liver parenchyma, was significantly reduced by vitamin D depletion. Control rat livers of both groups showed normal liver histology, and no foci, nodules or oval cells were detected in either group. The present data suggest that vitamin D depletion leads to increased in vivo susceptibility to chemicals known to induce hepatocarcinogenesis. Vitamin D depletion in rats caused changes on focus size, which was found to be significantly greater in vitamin D-depleted rat livers at weeks 2 to 6; focus area (volume fraction) was also found to be consistently larger in livers of vitamin D-depleted rats than in those of normal rats [16].
Breast cancer and vitamin D deficiency
Reduction of epidermal growth factor receptor (EGFR) mRNA and protein by 1,25-dihydroxyvitamin D3 has been documented in MCF7, T47D, and BT549 breast cancer cells [20].
5. (Ro)accutane and irreversible androgen deprivation: the effects on cancer susceptibility
(Ro)accutane is in repeated studies found to cause a DHT deficiency post exposure partially through a significant inhibition of 5-alpha-r [18 and more].
It was previously assumed that androgen deficiency would have only positive effects on susceptbility of prostate cancer. Over 60 years ago, Huggins and Hodges discovered androgen deprivation as a first-line therapy for metastatic prostate cancer, which leads to remissions typically lasting 2 to 3 years, but in most men prostate cancer ultimately progresses to an androgen-independent state resulting in death due to widespread metastases. Multiple mechanisms of androgen independence have now been documented, including amplification of the androgen receptor as well as signal transduction pathways that bypass the androgen receptor completely [19].
A recently published study has identified a doubled risk of cancer reoccurence in a large population with testicular cancer exposed to distinct cancer-treatments due to effects from the exposure. Statistically significantly increased risks of solid cancers were observed among patients treated with radiotherapy alone (RR = 2.0, 95% CI = 1.9 to 2.2), chemotherapy alone (RR = 1.8, 95% CI = 1.3 to 2.5), and both (RR = 2.9, 95% CI = 1.9 to 4.2) [1]. As of today, no study has evaluated the effects on cancer-susceptibility in subjects exposed to (Ro)accutane with no previous history of cancer. Hoffman la Roche itself, the distributor of (Ro)accutane sees no increased susceptibility for any type of cancer in (Ro)accutane exposed human subjects, but states that "new information may be available" [0].
At the moment, there is no direct evidence that would point out a drastically increased cancer-susceptibility in humans, however, the issue needs proper evaluation, since some studies are showing a direct connection between certain factors recognizable as results from (Ro)accutane exposure, such as vitamin D deficiency, with higher susceptibility for cancer. However, cancer susceptibility is a complex parameter, dependent on multiple variables as prognostic factors, often in combinations, and also different depending on type of cancer.
The effects regarding risks of cancer susceptibility later in life in (Ro)accutane exposed acne-subjects, with no previous history of cancer, are not known either at an empirical or a theoretical level. Various altered parameters in exposed subjects are pointing in opposite directions. This section is aimed at discussing how a (Ro)accutane exposure in acne-subjects may affect cancer susceptibility based on a set of known and discussed risk factors.
Generally can be said, that with the knowledge of today, the major parameters that talks against a higher susceptibility for certain cancers are certain hormonal deficiencys detected post (Ro)accutane exposure in human subjects, including androgen deficiency and thyroid deficiency. However, those parameters do not provide a fully intact result.
The paramaters talking for a higher cancer susceptibility can be described as the alterations in immune-function discovered in human subjects exposed to (Ro)accutane, including altered cytokine production, possibly altered macrophage activation and receptor malfunctions.
Vitamin A deficiency associated with higher incidence of cancer in experimental animals
Vitamin A deficiency in experimental animals has been associated with a higher incidence of cancer and with increased susceptibility to chemical carcinogens. This is in agreement with the epidemiological studies indicating that individuals with a lower dietary vitamin A intake are at a higher risk to develop cancer [2, 6 and more].
Loss of retinoid signaling and retinoid resistance due to lessened retinoid receptor function suggested to increase cancer susceptibility
Collections of data suggest that the RAR receptor acts as a tumour suppressor in several types of cancer, and confirm the role of retinoid signaling as important in cancer resistance [8 and more]. Tumour antigens such as PRAME may repress the retinoid receptor signaling and thus contribute to cancer development [10].
Exposure to retinoids in several types of cancer frequently lead to retinoid resistance and thus reoccurrence [9 and more]. These observations of retinoid resistance after heavy retinoid exposure may depend on a downregulation of retinoid receptor expression and coactivator function when supraphysiological doses of retinoids are administered to human subjects over time. After (Ro)accutane exposure in human acne-subjects, the expression of retinoid receptors, such as RAR receptors is surprisingly not either statistically or experimentally measured, but is likely to be significantly decreased. "In situ hybridization was used to compare retinoid receptor expression profiles in head and neck squamous cell carcinomas, dysplastic lesions, adjacent normal tissues, and in tissues from normal volunteers (Xu et al., 1994). RAR, RAR, and RAR and RXR and RXR mRNAs were expressed in all samples from normal volunteers. The levels of RAR and RAR and RXR and RXR mRNAs were similar to that in most of the adjacent normal, hyperplastic, dysplastic, and malignant tissues. However, RAR mRNA levels were detected in only 70% of dysplastic and adjacent normal tissues, and were repressed further in dysplastic and malignant epithelium. RAR repression was also found in preneoplastic oral cavity lesions (Lotan et al., 1995), non-small-cell lung cancer (Castillo et al., 1997; Xu et al., 1997a; Picard et al., 1999), breast cancers (Widschwendter et al., 1997; Xu et al., 1997b), and esophageal cancer (Qiu et al., 1999). Other retinoid receptors were expressed in these tissues, but only RAR levels were significantly lower in the premalignant and tumor tissues. The correlation of RAR repression with epithelial carcinogenesis led to the hypothesis that RAR could act as a tumor suppressor. This view was supported by experiments where RAR was overexpressed in cell lines. In retinoid-sensitive human lung carcinoma cells, constitutive overexpression of RAR2 inhibited cellular proliferation (Houle et al., 1993)" [8].
1. Possible increased risk for skin cancer, ultraviolet radiation induced tumours in subjects exposed to (Ro)accutane
Immunosuppressed patients are extremely susceptible to cutaneous squamous cell carcinoma, suggesting that immunosurveillance by T lymphocytes protects against this ultraviolet radiation-induced tumour. Both anti-CD8 and anti-CD4 treatment significantly enhanced the growth of transplanted tumours. In CD8-depleted animals, tumours grew rapidly in all animals. Tumour growth in CD4-depleted animals was slower, and 50% of these mice eventually rejected their tumours [3]. In transgenic mice local interruption of PML and RARalpha signaling in the skin, together with a systemic retinoid deficiency, initiates a tumor induction pathway that is independent of ras activation [4]. The major reason propounded for an association of sun exposure with a protective effect in the development of cancer and improved survival is that vitamin D synthesis is a critical component of cellular networks that inhibit cellular proliferation and encourage apoptosis [14].
2. Possible attenuated effects on lung cancer from outdoor airborne particulate matter (APM) and smoking in subjects exposed to (Ro)accutane
Findings of vitamin A status and possible attenuated effects from outdoor airborna particulate matter and smoking are pointing in different directions. The finnish ATBC study, involving a large population found that supplementation with supraphysiological doses of beta-carotene may modestly increase lung cancer incidence in cigarette smokers, and this effect may be associated with heavier smoking and higher alcohol intake [5].
However, the opposite, a pronounced vitamin A deficiency may be attenuated by APM. APM has the potency to deplete lung vitamin A in vivo and vitamin A might have a protective effect in the process of lung carcinogenesis, APM might increase the susceptibility for the development of lung cancer [6].
In mice, it was found that the the angiotensin II (AT2) receptor function in lung stromal fibroblasts may be a potential modulator of tumor susceptibility in chemical carcinogen-induced lung tumorigenesis. AT2 receptor null mice displayed higher susceptibility to lung cancer. The level of active TGF-beta in the conditioned medium was consistently higher with AT2-null fibroblasts than with wild-type fibroblasts [7]. The AT2 receptor is one of the receptors heavily affected from (Ro)accutane exposure, and its expression is suggested to be inhibited [8].
3. The metabolic syndrome, diabetes and cancer susceptibility
4. (Ro)accutane induced vitamin D deficiency and cancer susceptibility: suggested variations between type of cancer
A significant fall in the level of 1,25-dihydroxyvitamin D, and a significant increase in the molar ratio of 24, 25-dihydroxyvitamin D to 25-hydroxyvitamin D was found in human subjects after exposure to (Ro)accutane, indicating a (Ro)accutane induced significant 1,25-dihydroxyvitamin D deficiency [11].
Colon cancer and vitamin D deficiency
The relationship between vitamin D deficiency and colon cancer has been extensively shown [13, 15 and more]. In vitro and in vivo studies demonstrated that 1,25-dihydroxycholecalciferol [1,25(OH)(2)D(3)] and its analogs inhibit colon cancer cell proliferation. Vitamin D deficiency enhances the growth of colon cancer in mice. The tumor expression of VDR and 1alpha-OHase indicates possible autocrine/paracrine cell growth regulation by vitamin D [13].
Prostate cancer and vitamin D deficiency
Epidemiological evidence suggests that vitamin D deficiency also is associated with increased risk for prostate cancer. Results show that cholecalciferol, at physiological levels: (i) inhibits anchorage-dependent growth (ii) induces differentiation by increasing PSA expression and (iii) exerts its effects by up-regulating vitamin D receptor (VDR), retinoid-X receptors (RXRs), and androgen receptor (AR). Furthermore, it was discovered that human prostate epithelial cells constitutively express appreciable levels of 25-hydroxylase CYP27A1 protein, the enzyme which catalyzes the conversion of cholecalciferol to 25(OH)D(3), and that CYP27A1 is up-regulated by cholecalciferol. Recent studies show that human mitochondrial CYP27A1 can also catalyze 1alpha-hydroxylation of 25(OH)D(3) to calcitriol. The presence of 25-hydroxylase in human prostate epithelial cells has not previously been shown. Since human prostate epithelial cells have the necessary enzymes and the rare ability to locally convert cholecalciferol to the active hormone calcitriol, it is proposed that they are a prime target for chemoprevention of prostate cancer with cholecalciferol whose safety is well established as a supplement in vitamins and fortified foods [17].
1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) and its analogues have been shown to inhibit proliferation of human cancer cells mediated by vitamin D receptor (VDR). CYP24A1 mRNA was significantly up-regulated in colon, ovary and lung tumors, but down-regulated in breast tumor relative to the analogous normal tissues. As a comparison, VDR mRNA was modestly down-regulated in colon, breast and lung tumors, but highly up-regulated in ovarian tumors [12].
Hepatocarcinogenesis and vitamin D deficiency
In rats, labeling of oval cells, a cell compartment possibly associated with the repopulation of the liver parenchyma, was significantly reduced by vitamin D depletion. Control rat livers of both groups showed normal liver histology, and no foci, nodules or oval cells were detected in either group. The present data suggest that vitamin D depletion leads to increased in vivo susceptibility to chemicals known to induce hepatocarcinogenesis. Vitamin D depletion in rats caused changes on focus size, which was found to be significantly greater in vitamin D-depleted rat livers at weeks 2 to 6; focus area (volume fraction) was also found to be consistently larger in livers of vitamin D-depleted rats than in those of normal rats [16].
Breast cancer and vitamin D deficiency
Reduction of epidermal growth factor receptor (EGFR) mRNA and protein by 1,25-dihydroxyvitamin D3 has been documented in MCF7, T47D, and BT549 breast cancer cells [20].
5. (Ro)accutane and irreversible androgen deprivation: the effects on cancer susceptibility
(Ro)accutane is in repeated studies found to cause a DHT deficiency post exposure partially through a significant inhibition of 5-alpha-r [18 and more].
It was previously assumed that androgen deficiency would have only positive effects on susceptbility of prostate cancer. Over 60 years ago, Huggins and Hodges discovered androgen deprivation as a first-line therapy for metastatic prostate cancer, which leads to remissions typically lasting 2 to 3 years, but in most men prostate cancer ultimately progresses to an androgen-independent state resulting in death due to widespread metastases. Multiple mechanisms of androgen independence have now been documented, including amplification of the androgen receptor as well as signal transduction pathways that bypass the androgen receptor completely [19].