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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: 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.

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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Post molar pregnancy gestational trophoblast tumour. Pre and post treatment MRI scans of the pelvis showing a large uterine mass prior to treatment and a normal scan at completion. The treatment graph shows the fall and normalisation of the hCG level with low dose methotrexate chemotherapy treatment. The patient has completed treatment, gone on to have a healthy baby and has been cured of this malignancy.
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Fig1: Post molar pregnancy gestational trophoblast tumour. Pre and post treatment MRI scans of the pelvis showing a large uterine mass prior to treatment and a normal scan at completion. The treatment graph shows the fall and normalisation of the hCG level with low dose methotrexate chemotherapy treatment. The patient has completed treatment, gone on to have a healthy baby and has been cured of this malignancy.

Mentions: Low dose methotrexate was first successfully used in the treatment of post molar pregnancy gestational trophoblast tumours in 1956 [2] and protocols based on low dose methotrexate remain the standard of care at most treatment centres [29,59]. A routine example of the rapid response treatment and curative outcome for a patient with post molar pregnancy gestational trophoblast tumours is shown in Figure 1. Overall 100% of patients with post molar pregnancy gestational trophoblast tumours can be cured with chemotherapy, with the majority only requiring therapy with doses of methotrexate that would be sub-therapeutic and have little activity in other malignancies [29].Figure 1


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

Savage P - BMC Cancer (2015)

Post molar pregnancy gestational trophoblast tumour. Pre and post treatment MRI scans of the pelvis showing a large uterine mass prior to treatment and a normal scan at completion. The treatment graph shows the fall and normalisation of the hCG level with low dose methotrexate chemotherapy treatment. The patient has completed treatment, gone on to have a healthy baby and has been cured of this malignancy.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig1: Post molar pregnancy gestational trophoblast tumour. Pre and post treatment MRI scans of the pelvis showing a large uterine mass prior to treatment and a normal scan at completion. The treatment graph shows the fall and normalisation of the hCG level with low dose methotrexate chemotherapy treatment. The patient has completed treatment, gone on to have a healthy baby and has been cured of this malignancy.
Mentions: Low dose methotrexate was first successfully used in the treatment of post molar pregnancy gestational trophoblast tumours in 1956 [2] and protocols based on low dose methotrexate remain the standard of care at most treatment centres [29,59]. A routine example of the rapid response treatment and curative outcome for a patient with post molar pregnancy gestational trophoblast tumours is shown in Figure 1. Overall 100% of patients with post molar pregnancy gestational trophoblast tumours can be cured with chemotherapy, with the majority only requiring therapy with doses of methotrexate that would be sub-therapeutic and have little activity in other malignancies [29].Figure 1

Bottom Line: 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.

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