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Clinical observations on chemotherapy curable malignancies: unique genetic events, frozen development and enduring apoptotic potential.

Savage P - BMC Cancer (2015)

Bottom Line: A select number of relatively rare metastatic malignancies comprising trophoblast tumours, the rare childhood cancers, germ cells tumours, leukemias and lymphomas have been routinely curable with chemotherapy for more than 30 years.In the chemotherapy curable malignancies the onset of malignancy is in each case closely linked to one of the unique genetic events of; nuclear fusion for molar pregnancies, choriocarcinoma and placental site trophoblast tumours, gastrulation for the childhood cancers, meiosis for testicular cancer and ovarian germ cell tumours and VDJ rearrangement and somatic hypermutation for acute leukemia and lymphoma.These processes are all linked to natural periods of supra-physiological apoptotic potential and it appears that the malignant cells arising from them usually retain this heightened sensitivity to DNA damage.

View Article: PubMed Central - PubMed

Affiliation: BCCA Vancouver Island, 2410 Lee Avenue, Victoria, BC, V8R 6V5, Canada. savage13561@msn.com.

ABSTRACT

Background: A select number of relatively rare metastatic malignancies comprising trophoblast tumours, the rare childhood cancers, germ cells tumours, leukemias and lymphomas have been routinely curable with chemotherapy for more than 30 years. However for the more common metastatic malignancies chemotherapy treatment frequently brings clinical benefits but cure is not expected. Clinically this clear divide in outcome between the tumour types can appear at odds with the classical theories of chemotherapy sensitivity and resistance that include rates of proliferation, genetic development of drug resistance and drug efflux pumps. We have looked at the clinical characteristics of the chemotherapy curable malignancies to see if they have any common factors that could explain this extreme differential sensitivity to chemotherapy.

Discussion: It has previously been noted how the onset of malignancy can leave malignant cells fixed with some key cellular functions remaining frozen at the point in development at which malignant transformation occurred. In the chemotherapy curable malignancies the onset of malignancy is in each case closely linked to one of the unique genetic events of; nuclear fusion for molar pregnancies, choriocarcinoma and placental site trophoblast tumours, gastrulation for the childhood cancers, meiosis for testicular cancer and ovarian germ cell tumours and VDJ rearrangement and somatic hypermutation for acute leukemia and lymphoma. These processes are all linked to natural periods of supra-physiological apoptotic potential and it appears that the malignant cells arising from them usually retain this heightened sensitivity to DNA damage. To investigate this hypothesis we have examined the natural history of the healthy cells during these processes and the chemotherapy sensitivity of malignancies arising before, during and after the events. To add to the debate on chemotherapy resistance and sensitivity, we would argue that malignancies can be functionally divided into 2 groups. Firstly those that arise in cells with naturally heightened apoptotic potential as a result of their proximity to the unique genetic events, where the malignancies are generally chemotherapy curable and then the more common malignancies that arise in cells of standard apoptotic potential that are not curable with classical cytotoxic drugs.

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Advanced testicular cancer. Pre and post treatment CT scans of the chest showing multiple pulmonary lesions at diagnosis and virtual resolution of the lesions by the time of completion of chemotherapy. The treatment graph shows the decline and normalisation of hCG levels with BEP chemotherapy treatment. Nine years on the patient is in a complete remission, and is almost certainly cured. The lung lesions resolved completely with longer follow up.
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Fig3: Advanced testicular cancer. Pre and post treatment CT scans of the chest showing multiple pulmonary lesions at diagnosis and virtual resolution of the lesions by the time of completion of chemotherapy. The treatment graph shows the decline and normalisation of hCG levels with BEP chemotherapy treatment. Nine years on the patient is in a complete remission, and is almost certainly cured. The lung lesions resolved completely with longer follow up.

Mentions: Metastatic testicular cancer has been potentially curable with chemotherapy since the 1960s [87] and modern treatment now brings overall cure rates exceeding 80% [88,89]. A routine example case of a patient cured of intermediate risk testicular cancer is shown in Figure 3. Similarly in women, advanced ovarian germ cell tumours, whilst much rarer, are also effectively treated with combination chemotherapy with overall cure rates of approximately 80% [33]. In both diagnoses the most widely used regimen of BEP comprises bleomycin, etoposide, and cisplatin, which are three conventional cytotoxic drugs all introduced into routine care prior to the mid-1980s [32,33].Figure 3


Clinical observations on chemotherapy curable malignancies: unique genetic events, frozen development and enduring apoptotic potential.

Savage P - BMC Cancer (2015)

Advanced testicular cancer. Pre and post treatment CT scans of the chest showing multiple pulmonary lesions at diagnosis and virtual resolution of the lesions by the time of completion of chemotherapy. The treatment graph shows the decline and normalisation of hCG levels with BEP chemotherapy treatment. Nine years on the patient is in a complete remission, and is almost certainly cured. The lung lesions resolved completely with longer follow up.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4308945&req=5

Fig3: Advanced testicular cancer. Pre and post treatment CT scans of the chest showing multiple pulmonary lesions at diagnosis and virtual resolution of the lesions by the time of completion of chemotherapy. The treatment graph shows the decline and normalisation of hCG levels with BEP chemotherapy treatment. Nine years on the patient is in a complete remission, and is almost certainly cured. The lung lesions resolved completely with longer follow up.
Mentions: Metastatic testicular cancer has been potentially curable with chemotherapy since the 1960s [87] and modern treatment now brings overall cure rates exceeding 80% [88,89]. A routine example case of a patient cured of intermediate risk testicular cancer is shown in Figure 3. Similarly in women, advanced ovarian germ cell tumours, whilst much rarer, are also effectively treated with combination chemotherapy with overall cure rates of approximately 80% [33]. In both diagnoses the most widely used regimen of BEP comprises bleomycin, etoposide, and cisplatin, which are three conventional cytotoxic drugs all introduced into routine care prior to the mid-1980s [32,33].Figure 3

Bottom Line: A select number of relatively rare metastatic malignancies comprising trophoblast tumours, the rare childhood cancers, germ cells tumours, leukemias and lymphomas have been routinely curable with chemotherapy for more than 30 years.In the chemotherapy curable malignancies the onset of malignancy is in each case closely linked to one of the unique genetic events of; nuclear fusion for molar pregnancies, choriocarcinoma and placental site trophoblast tumours, gastrulation for the childhood cancers, meiosis for testicular cancer and ovarian germ cell tumours and VDJ rearrangement and somatic hypermutation for acute leukemia and lymphoma.These processes are all linked to natural periods of supra-physiological apoptotic potential and it appears that the malignant cells arising from them usually retain this heightened sensitivity to DNA damage.

View Article: PubMed Central - PubMed

Affiliation: BCCA Vancouver Island, 2410 Lee Avenue, Victoria, BC, V8R 6V5, Canada. savage13561@msn.com.

ABSTRACT

Background: A select number of relatively rare metastatic malignancies comprising trophoblast tumours, the rare childhood cancers, germ cells tumours, leukemias and lymphomas have been routinely curable with chemotherapy for more than 30 years. However for the more common metastatic malignancies chemotherapy treatment frequently brings clinical benefits but cure is not expected. Clinically this clear divide in outcome between the tumour types can appear at odds with the classical theories of chemotherapy sensitivity and resistance that include rates of proliferation, genetic development of drug resistance and drug efflux pumps. We have looked at the clinical characteristics of the chemotherapy curable malignancies to see if they have any common factors that could explain this extreme differential sensitivity to chemotherapy.

Discussion: It has previously been noted how the onset of malignancy can leave malignant cells fixed with some key cellular functions remaining frozen at the point in development at which malignant transformation occurred. In the chemotherapy curable malignancies the onset of malignancy is in each case closely linked to one of the unique genetic events of; nuclear fusion for molar pregnancies, choriocarcinoma and placental site trophoblast tumours, gastrulation for the childhood cancers, meiosis for testicular cancer and ovarian germ cell tumours and VDJ rearrangement and somatic hypermutation for acute leukemia and lymphoma. These processes are all linked to natural periods of supra-physiological apoptotic potential and it appears that the malignant cells arising from them usually retain this heightened sensitivity to DNA damage. To investigate this hypothesis we have examined the natural history of the healthy cells during these processes and the chemotherapy sensitivity of malignancies arising before, during and after the events. To add to the debate on chemotherapy resistance and sensitivity, we would argue that malignancies can be functionally divided into 2 groups. Firstly those that arise in cells with naturally heightened apoptotic potential as a result of their proximity to the unique genetic events, where the malignancies are generally chemotherapy curable and then the more common malignancies that arise in cells of standard apoptotic potential that are not curable with classical cytotoxic drugs.

Show MeSH
Related in: MedlinePlus