A Comparative Study of the Response to Radiation by Experimental Tumors with Markedly Different Growth Characteristics

Kovacs, C. J.; Evans, Mark J.; Wakefield, Jean A.; Looney, William B.

doi:10.2307/3574610

Cited by 10 publications

(3 citation statements)

References 31 publications

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“…These findings demonstrated the second property of cancer stem cells noted above, i.e., tumor initiation. Finally, extensive studies on the response to irradiation treatment by William Looney (88) demonstrated that after high-dose radiation, the tumors were able to re-grow, indicating the presence of a therapy-resistant cancer stem cell. Thus, these studies published in the 1960s and 70s demonstrated that Morris hepatomas contained cancer stem cells (see below for more recent studies on cancer stem cells in human hepatomas).…”

Section: Afp Production By Hepatocellular Carcinomasmentioning

confidence: 99%

Alpha-Fetoprotein, Stem Cells and Cancer: How Study of the Production of Alpha-Fetoprotein during Chemical Hepatocarcinogenesis Led to Reaffirmation of the Stem Cell Theory of Cancer

Sell¹

2008

Tumor Biol

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Identification of the cells in the liver that produce α-fetoprotein during development, in response to liver injury and during the early stages of chemical hepatocarcinogenesis led to the conclusion that maturation arrest of liver-determined tissue stem cells was the cellular process that gives rise to hepatocellular carcinomas. When the cellular changes in these processes were compared to that of the formation of teratocarcinomas, the hypothesis arose that all cancers arise from maturation arrest of tissue-determined stem cells. This was essentially a reinterpretation of the embryonal rest theory of cancer whereby tissue stem cells take the role of embryonal rests. A corollary of the stem cell theory of the origin of cancer is that cancers contain the same functional cell populations as normal tissues: stem cells, transit-amplifying cells and mature cells. Cancer stem cells retain the essential feature of normal stem cells: the ability to self-renew. Growth of cancers is due to continued proliferation of cancer transit-amplifying cells that do not differentiate to mature cells (maturation arrest). On the other hand, cancer stem cells generally divide very rarely and contribute little to tumor growth. However, the presence of cancer stem cells in tumors is believed to be responsible for the properties of immortalization, transplantability and resistance to therapy characteristic of cancers. Current therapies for cancer (chemotherapy, radiotherapy, antiangiogenesis and differentiation therapy) are directed against the cancer transit-amplifying cells. When these therapies are discontinued, the cancer reforms from the cancer stem cells. Therapy directed toward interruption of the cell signaling pathways that maintain cancer stem cells could lead to new modalities to the prevention of regrowth of the cancer.

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Section: Afp Production By Hepatocellular Carcinomasmentioning

confidence: 99%

Alpha-Fetoprotein, Stem Cells and Cancer: How Study of the Production of Alpha-Fetoprotein during Chemical Hepatocarcinogenesis Led to Reaffirmation of the Stem Cell Theory of Cancer

Sell¹

2008

Tumor Biol

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“…The increased efficacy of fractionated pretreatment with ICRF-159 before radiation over acutely administered drug+ radiation is seen in Fig. 8 (Denekamp, 1972;Kovacs et al, 1977), tumour regression and the accompanying regrowth delay, as seen in Fig. 8, demonstrate the superiority of fractionated over acute pretreatment with ICRF-159 before radiotherapy.…”

mentioning

confidence: 86%

ICRF-159 enhancement of radiation response in combined modality therapies. I. Time/dose relationships for tumour response

Kovacs¹,

Evans²,

Schenken³

et al. 1979

Br J Cancer

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Summary-The combined effect of the chemotherapeutic agent ICRF-159 and irradiation were evaluated using the Lewis lung tumour (LL). At a daily dose of 25 mg/kg, ICOF given alone prevented the progressive growth of LL. Daily pretreatment also potentiated the effects of radiation (600 rad) on tumour growth, provided the pretreatment kinetics of the tumour permitted a response to radiation alone. Single acute doses of the drug failed to alter the growth of LL, and when combined with radiation failed to enhance the radiation effect. Fractionation of the drug (25 mg/kg; 4 doses at 3h intervals) before irradiation, however, results in immediate effects on tumour growth which are more than additive. The results suggest that a low dose of ICRF-159 for extended periods is more effective in enhancing radiotherapy than a high dose provided acutely.

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“…Studies (Kovacs et al, 1977 Marrow evaluation.-At various times after injection of 150 mg/kg of FU, groups of 3 rats each were injected i.p. with 50 HCi thymidine-(methyl)-3H (sp.…”

mentioning

confidence: 99%

Solid Tumour Models for the Assessment of Different Treatment Modalities: vii: Single vs Fractionated Doses of 5-Fluorouracil on Two Solid Tumours and Their Hosts

Looney¹,

MacLeod²,

Hopkins³

1978

Br J Cancer

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Summary.-The effects of one large single dose of 5-fluorouracil (FU) have been compared to the same amount given in divided doses daily over a 3-or 5-day period.Comparison of the effects of single vs fractionated dosage was made on 2 types of experimental solid tumour with different growth, cell kinetic, histological and metastasizing properties. The tumour response was essentially the same for both the single and fractionated dose schedules.There were marked increases in animal mortality from drug toxicity following fractionated doses of FU compared to one large single dose. Mortality in animals with Tumour 3924A increased from 10% following one large single dose to 600/ for animals given daily fractionated doses for 3 days, and 80o/ for animals given daily fractionated doses for 5 days. Total marrow reserve was measured by the total DNA content of tibial marrow. The nadir of 6 days for loss of total tibial marrow DNA following one large dose of FU was increased to 9 days for both fractionated schedules of FU. The 3-day delay in recovery of the marrow prevented recovery within the time frame necessary for animal survival. The inference from these experimental cancertreatment studies is that daily fractions of chemotherapeutic agents such as FU result in increased morbidity and mortality, without benefit in the control of the solid tumour. The results question the advisability of the clinical practice of initially giving small daily "loading doses" of proliferation-dependent agents such as FU.These results emphasize the need for more precise information on the temporal relationship between the response and recovery of the host and the response and recovery of the solid tumour. They also emphasize the need for a better clinical understanding of the time sequence of solid-tumour recovery in relation to the time sequence of marrow recovery."ALTHOUGH 5-fluorouracil (FU) has been used clinically since 1957, there presently exists a wide divergence in opinion among individual investigators, institutions, and-cooperative groups about the optimal dosage regimen" (Ansfield et al., 1977). Initial "loading doses" of FU and other proliferation-dependent cancerchemotherapeutic agents are given daily or on alternate days and pushed to the point of mild toxicity. This approach to the clinical management of cancer patients uses, in most instances, host toxicity as the primary guide for the scheduling of the proliferation-dependent chemotherapy agents such as FU. Quantitative assessment of tumour response is often difficult or impossible. It is evident that more precise information on the temporal relationship between the response and recovery of the host and the response and recovery of the tumour is needed for a more rational design of clinical protocols.Studies on the effects of FU on experimental solid tumours have been carried out, to determnine quantitatively the effect of increasing doses of FU on tumour growth, animal morbidity and mortality. The ability to evaluate quantitatively the effects of different schedules of F...

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A Comparative Study of the Response to Radiation by Experimental Tumors with Markedly Different Growth Characteristics

Cited by 10 publications

References 31 publications

Alpha-Fetoprotein, Stem Cells and Cancer: How Study of the Production of Alpha-Fetoprotein during Chemical Hepatocarcinogenesis Led to Reaffirmation of the Stem Cell Theory of Cancer

Alpha-Fetoprotein, Stem Cells and Cancer: How Study of the Production of Alpha-Fetoprotein during Chemical Hepatocarcinogenesis Led to Reaffirmation of the Stem Cell Theory of Cancer

ICRF-159 enhancement of radiation response in combined modality therapies. I. Time/dose relationships for tumour response

Solid Tumour Models for the Assessment of Different Treatment Modalities: vii: Single vs Fractionated Doses of 5-Fluorouracil on Two Solid Tumours and Their Hosts

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