Metastasis of a transplantable mammary tumour in rats treated with cyclophosphamide and/or irradiation

Moore, James; Dixon, B.

doi:10.1038/bjc.1977.181

Cited by 40 publications

(14 citation statements)

References 12 publications

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“…In general, the pattern of spread and overall incidence of metastases observed for LMC1 after excision was similar to the data obtained when the primary tumour was left in situ and irradiated locally with 60Co gamma-rays and/or the host was pretreated with cyclophosphamide (Moore & Dixon 1977a). In that study, treatment with drug appeared to enhance the incidence of metastases and facilitate their more widespread distribution, compared to the effect of irradiation alone.…”

Section: Resultssupporting

confidence: 81%

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Local Recurrence and Metastasis of Excised Breast Carcinoma in the Rat

Dixon

Speakman

1979

J R Soc Med

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Section: Resultssupporting

confidence: 81%

“…We have also shown that the incidence of metastases from this tumour is higher if systemic cyclophosphamide is given 4 to 10 days before local irradiation (Moore & Dixon 1977a).…”

Section: Introductionmentioning

confidence: 62%

Local Recurrence and Metastasis of Excised Breast Carcinoma in the Rat

Dixon

Speakman

1979

J R Soc Med

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“…These data on cyclophosphamide, together with the previously published reports of CP inhancement of artificial pulmonary metastases with a variety of tumours (van Putten et al, 1975;Carmel and Brown, 1977;Peters and Mason, 1977), and the recent report of enhanced spontaneous metastasis in rat tumours treated with various doses of CP (Moore and Dixon, 1977), serve to underline the potential hazards of clinical use of CP. Clearly, it is a potent cytotoxic agent and will be beneficial when delivered to preexisting metastases.…”

Section: Discussionsupporting

confidence: 53%

“…It has also been reported that CP can increase spontaneous metastases from a weakly-or non-immunogenic transplanted rat tumour (Moore and Dixon, 1977). Again, however, the doses employed in these studies were single doses and, on the basis of body weight (mg/kg) (althouglh not on surface area), were higher than could be given to humans.…”

mentioning

confidence: 88%

Effect of Dose Fractionation on the Enhancement by Radiation or Cyclophosphamide of Artificial Pulmonary Metastases

Brown¹,

Marsa²

1978

Br J Cancer

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Summary.-Thoracic irradiation or cyclophosphamide (CP) treatment of mice before an i.v. injection of tumour cells enhances the number of lung colonies produced by a factor of up to 100+. The effect of fractionation of the X-ray or CP dose on this phenomenon was investigated in several ways.The dose-response curve for the number of lung colonies as a function of the dose of thoracic irradiation was linear, and the degree of enhancement was independent of the number of tumour cells injected. Splitting a dose of 1,000 rad into 2 equal fractions separated by times varying from 1 to 24 h gave the same enhancement as that produced by a single dose of 1000 rad. Similarly, fractionation of 1000 rad into 5 x 200 rad, or 2000 rad into 5 x 400 rad (each interval between fractions being 3 h) had no effect on the radiation enhancement of colony formation.A single dose of 200 mg/kg of CP was compared with 3 doses of 66-7 mg/kg (each dose separated by 12 h) and with a continuous infusion of 200 mg/kg given over 24 h. In this case, fractionation and infusion produced a small reduction in the CP-induced increase, but the factor of colony enhancement compared to control mice remained >100.These data emphasize the potential hazard of prophylactic treatment of pulmonary metastases by X-rays or CP in clinical situations in which control of the primary tumour is not achieved.IT HAS BEEN SHOWN conclusively that irradiation of the lungs of mice and rats increases the number of pulmonary nodules ("artificial metastases") arising from a subsequent i.v. injection of tumour cells (Fidler and Zeidman, 1972;Brown, 1973a; Withers and Milas, 1973;van den Brenk et al., 1973;Peters, 1974;Thompson, 1974). It has also been shown that prophylactic X-irradiation of the lungs of dogs with spontaneous osteosarcomas results in more metastases than in unirradiated lungs, in situations in which the primary tumour is not cured (Owen and Bostock, 1973). All authors are agreed that the enhancement of pulmonary metastases produced by local thoracic irradiation is not due to suppression of any specific immune response against the tumour.Although it has been claimed by several of the above authors that this effect might have clinical relevance in the situation in which prophylactic lung irradiation has been given, this remains speculative. One reason for questioning the clinical relevance of the findings to date is that, with one exception, in each study only large or moderately large single doses of irradiation were given. In the study which is the exception, van den Brenk and Kelley (1974) showed that a fractionated regime of 5 x 350 rad spread over 9 days produced a greater enhancement of lung colonies than a single dose of 1250 rad. However, * Present address: Toledo Radiological Associates Inc., Toledo, Ohio 43606.

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“…Van Putten et al 31 showed that treatment of animals bearing a transplantable osteosarcoma with cyclophosphamide or CCNU resulted in a significant increase in lung metastases compared to controls. Following these initial observations, enhancement of metastases was also obtained in other tumour systems with cyclophosphamide 32,33 and bleomycin. 34,35 De Larco et al 36 developed MCF-7A/F by treating the parental MCF-7 cell line sequentially with doxorubicin and 5-fluoro-2Ј-deoxyuridine in vitro and found that the MCF-7A/F cells in vivo had a more rapid initial growth phase in situ and gave rise to spontaneous lung metastases within 10 weeks, while MCF-7 cells were not able to form metastases.…”

Section: Discussionmentioning

confidence: 86%

Enhanced in vitro invasiveness and drug resistance with altered gene expression patterns in a human lung carcinoma cell line after pulse selection with anticancer drugs

Liang

O’Driscoll

McDonnell

et al. 2004

Intl Journal of Cancer

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The human lung carcinoma cell line DLKP was exposed to sequential pulses of 10 commonly used chemotherapeutic drugs (VP-16, vincristine, taxotere, mitoxantrone, 5-fluorouracil, methotrexate, CCNU, BCNU, cisplatin and chlorambucil); resulting cell lines exhibited resistance to the selecting agents (ranging approx. 1.5-to 36-fold) and, in some cases, cross-resistance to methotrexate (approx. 1.4-to 22-fold), vincristine (1.6-to 262-fold), doxorubicin (Adriamycin, approx. 1.1-to 33-fold) and taxotere (approx. 1.1-to 36-fold). Several of the variants displayed collateral sensitivity to cisplatin. A marked increase in in vitro invasiveness and motility was observed with variants pulsed with mitoxantrone, 5-fluorouracil, methotrexate, BCNU, cisplatin and chlorambucil. There was no significant change in invasiveness of cells pulsed with VP-16, vincristine, taxotere or CCNU. All of the pulseselected variants showed elevated levels of MDR-1/P-gp protein by Western blot analysis, although mdr-1 mRNA levels were not increased (except for DLKP-taxotere). In DLKPtaxotere, MRP1 protein levels were also greatly elevated, but mrp1 mRNA levels remained unchanged. BCRP was upregulated in DLKP-mitoxantrone at both the mRNA and protein levels. Gelatin zymography, Western blot and RT-PCR showed that DLKP and its variants secreted MMPs 2, 9 and 13. MMP inhibition assays suggested that MMP-2 plays a more important role than MMPs 9 and 13 in cell invasion of these DLKP drug-resistant variants in vitro. Reducing intracellular drug levels, often associated with overexpression of P-gp, 3 members of the MRP family 4 and the BCRP/ MXR protein, 5 is an important and frequent mechanism of MDR.Invasion through basement membrane is believed to be a critical step in metastasis. There are 4 main classes of proteases involved in proteolytic degradation of the ECM: serine-, cysteine-and aspartyl-proteases as well as MMPs. 6 The MMPs are a family of more than 20 members produced by tumour cells, connective tissue cells and inflammatory cells. MMPs are secreted as latent proenzymes and activated by proteolytic removal of an aminoterminal domain. 7 A large body of evidence shows that MMPs play a crucial role in cancer invasion and metastasis. Based on sequence homology and substrate specificity, MMP-2 and MMP-9 are classified as type IV collagenases that degrade the major component (type IV collagen) of basement membrane; 8 MMP-13, also called "collagenase-3", belongs to a group known as interstitial collagenases, which degrade collagen types I, II, III, VII, VIII and X. 9 The possibility of a relationship between drug resistance and invasion/metastasis phenotypes has been raised by 2 types of observation: 10 firstly, some tumour cells selected for resistance to drugs are invasive/metastatic relative to nonresistant parental cells; secondly, in some cases, secondary (more metastatic) tumours are more resistant to chemotherapeutic drugs than their primary counterparts. In support of this, Osmak et al. 11 reported a study of drug-resistant cervical and ...

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Metastasis of a transplantable mammary tumour in rats treated with cyclophosphamide and/or irradiation

Cited by 40 publications

References 12 publications

Local Recurrence and Metastasis of Excised Breast Carcinoma in the Rat

Local Recurrence and Metastasis of Excised Breast Carcinoma in the Rat

Effect of Dose Fractionation on the Enhancement by Radiation or Cyclophosphamide of Artificial Pulmonary Metastases

Enhanced in vitro invasiveness and drug resistance with altered gene expression patterns in a human lung carcinoma cell line after pulse selection with anticancer drugs

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