Showing papers by "Rakesh K. Jain published in 1988"

Determinants of Tumor Blood Flow: A Review

Abstract: Blood flow rate in a vascular network is proportional to the pressure difference between the arterial and venous sides and inversely proportional to the viscous and geometric resistances. Despite rapid progress in recent years, there is a paucity of quantitative data on these three determinants of blood flow in tumors and several questions remain unanswered. This paper reviews our current knowledge of these three parameters for normal and neoplastic tissues, the methods of their measurements, and the implications of the results in the growth and metastasis formation as well as in the detection and treatment of tumors. Microvascular pressures in the arterial side are nearly equal in tumor and nontumorous vessels. Pressures in venular vessels, which are numerically dominant in tumors, are significantly lower in a tumor than those in a nontumorous tissue. Decreased intravascular pressure and increased interstitial pressure in tumors are partly responsible for the vessel collapse as well as the flow stasis and reversal in tumors. The apparent viscosity (viscous resistance) of blood is governed by the viscosity of plasma and the number, size, and rigidity of blood cells. Plasma viscosity can be increased by adding certain solutes. The concentration of cells can be increased by adding cells to blood or by reducing plasma volume. The rigidity of RBC, which are numerically dominant in blood, can be increased by lowering pH, elevating temperature, increasing extracellular glucose concentration, or making the suspending medium hypo- or hypertonic. Effective size of blood cells can be increased by forming RBC aggregates (also referred to as rouleaux). RBC aggregation can be facilitated by lowering the shear rate (i.e., decreasing velocity gradients) or by adding macromolecules (e.g., fibrinogen, globulins, dextrans). Since cancer cells and WBC are significantly more rigid than RBC, their presence in a vessel may also increase blood viscosity and may even cause transient stasis. Finally, due to the relatively large diameters of tumor microvessels the Fahraeus effect (i.e., reduction in hematocrit in small vessels) and the Fahraeus-Lindqvist effect (i.e., reduction in blood viscosity in small vessels) may be less pronounced in tumors than in normal tissues. Geometric resistance for a network of vessels is a complex function of the vascular morphology, i.e., the number of vessels of various types, their branching pattern, and their length and diameter. Geometric resistance to flow in a single vessel is proportional to the vessel length and inversely proportional to vessel diameter to the fourth power.(ABSTRACT TRUNCATED AT 400 WORDS)

Mechanisms of Heterogeneous Distribution of Monoclonal Antibodies and Other Macromolecules in Tumors: Significance of Elevated Interstitial Pressure

Abstract: The therapeutic efficacy of monoclonal antibodies (MAbs), bound to radionuclides, chemotherapeutic agents, toxins, growth factors, or effector antibodies, depends upon their ability to reach their target in vivo in adequate quantities. Despite the high vascular permeability and interstitial transport coefficients in tumor tissue compared to several normal tissues, MAbs and their fragments do not distribute homogeneously in a tumor. Heterogeneity of tumor-associated antigen expression alone cannot explain this maldistribution of MAbs in tumors. We propose that in addition to the heterogeneous blood perfusion, hindered diffusion in the interstitium, and extravascular binding of MAbs, elevated interstitial pressure is responsible for the poor penetration of MAbs into tumors. Elevated interstitial pressure principally reduces the driving force for extravasation of fluid and macromolecules in tumors, and also leads to an experimentally verifiable, radially outward convection which opposes the inward diffusion. We present here mathematical models for transport of fluid and macromolecules in a tumor. To illustrate the significance of elevated interstitial pressure, these models are used to describe the interstitial pressure, interstitial fluid velocity, and concentration of nonbinding macromolecules as a function of radial position in a uniformly perfused tumor. The key result of these models is that the filtration of fluid from blood vessels in a uniformly perfused tumor is (a) spatially heterogeneous, (b) a result of elevated interstitial pressure, and (c) sufficient to explain the heterogeneous distribution of macromolecules in tumors. Nonuniform blood flow, and extravascular binding would enhance this heterogeneity in the solute distribution considerably. The results of the models also agree with the following experimental data: (a) tumor interstitial pressure is low in the periphery and it increases toward the center of the tumor; (b) the radially outward fluid velocity at the tumor periphery predicted by the model is of the same order of magnitude as measured in tissue-isolated tumors; and (c) immediately after bolus injection, the concentration of macromolecules is higher in the periphery than in the center; however, at later time periods the peripheral concentration is lower than in the center. These results have significant implications not only for MAbs and their fragments, but for other biologically useful macromolecules (e.g., cytokines) produced by genetic engineering for cancer diagnosis and treatment.

Response of tumours to hyperglycaemia: characterization, significance and role in hyperthermia

Abstract: The response of both neoplastic and surrounding normal tissue to hyperthermia is influenced by a number of physical, physiological, biological and immunological factors. Two physiological factors that play an important role are blood flow and pH. Temperature distributions within neoplastic and surrounding normal tissue during hyperthermia are influenced by convective heat transfer between the blood and tissue bed. A number of in vitro studies have illustrated that lowering media pH sensitizes cells to hyperthermia. It has been suggested that pharmacological agents could be used in conjunction with hyperthermia treatment to improve cancer treatment if these agents decrease tumour blood flow and/or decrease tumour pH. One agent that has been studied extensively for this purpose is glucose. The objective of this paper is to review the results on the effect of hyperglycaemia on normal and tumour tissue blood flow and pH and its role in hyperthermia. After a brief discussion of the role of tumour pH and blood ...

Blood Flow and Venous pH of Tissue-isolated Walker 256 Carcinoma during Hyperglycemia

Abstract: Hemodynamic (blood flow rate, hematocrit, hemoglobin concentration, and blood viscosity) and pH responses to glucose (6 g/kg, i.p.) injections were studied in ten Walker 256 carcinoma tumors (0.5–1.8 g) grown in the “tissue-isolated” tumor preparation. A maximum blood flow reduction of 57 ± 19% (SD) occurred concurrently with an increase in tumor arterial-venous blood pH difference 20–30 min after glucose administration. Tumor venous blood pH dropped significantly by 0.15 ± 0.07 pH unit to 7.15 ± 0.01, while systemic blood pH dropped by 0.06 ± 0.02 pH unit to 7.38 ± 0.03. Arteriovenous blood pH differences were found to correlate with blood flow rates; however, both the small magnitude of the pH reduction and the immediate blood flow response argue against the hypothesis of increased resistance to flow caused by low pH-stiffened RBC membranes. Significant increases in systemic and tumor efferent whole blood viscosities at 2.25 and 4.5s-1 occurred after glucose administration, while hemoglobin concentrations of systemic and tumor efferent blood increased by as much as 11 ± 1 and 16 ± 2%, respectively. Venous to arterial hematocrit and hemoglobin ratios remained unchanged with glucose administration. These data suggest local tumor blood flow reductions are caused by increased viscous resistance to flow within the tortuous microvasculature of tumor, not as a result of low pH RBC rigidity, but rather from other mechanisms such as glucose-mediated RBC rigidity and systemic hemoconcentration.

Transvascular and interstitial transport in tumors.

Abstract: The advent of hybridoma technology and genetic engineering has led to a large scale production of monoclonal antibodies and other biologically useful molecules. Some of these molecules can bind to intra-or extracellular sites in tumors for detection and treatment, while others (e.g., lymphokines) have the ability to activate certain immune cells for killing cancer cells. Since these molecules or cells do not have the biological selectivity for tumors in vivo as previously envisioned, methods must be developed to deliver them selectively to the target in vivo. Since no molecule or cell can reach the tumor cells without passing through the vascular and interstitial compartments, it seems reasonable to find out more about the structure and function of these two compartments. In the past few years, we have focused our research on the experimental and mathematical characterization of transport through these spaces. I would like to share the results of some of these studies with you, and point out their implications for tumor growth, detection and treatment.

Rapid, multistep rearrangements of hydrocarbon triplet biradicals at 4 K. A possible example of hot molecule effects in frozen organic solvents

Abstract: La photolyse de diaza-2,3bicyclo [221] heptenes-2 avec des groupes spirocyclopropyl en position 7 donne des diradicaux alkylidene-2 cyclopentanediyles-1,3

Topical Human Placental Extract For the Treatment of Vitiligo.

Abstract: Fifty percent human placental hydroalcoholic extract was used topically on 34 vitiligo patients. Complete clearing of lesions was seen in 20.6% cases, whereas 50% cases showed mild to moderate improvement, and 29.4% showed no response. No serious side effects were seen in any of the patients.

Effect of galactose on systemic hemodynamics and blood flow rate in normal and tumor tissues in rats.

Abstract: The effect of hyperglycemia on systemic hemodynamics and blood flow rate of Walker 256 carcinoma and several normal tissues of unanesthetized, unrestrained female Sprague-Dawley rats was measured, using the radioactive microsphere technique prior to and at 30 and 60 min after glucose administration (6 g/kg body weight i.v.). Whereas the mean arterial pressure and heart rate remained unchanged following glucose injection, cardiac output (CO), cardiac index, and stroke volume decreased by approximately 25% (P less than 0.05), and the total peripheral resistance increased by more than 25% (P less than 0.05). Redistribution of blood flow, expressed as a percentage of CO, among normal tissues was traced to the brain, kidneys, spleen, and liver and away from the skin, pancreas, and stomach. Changes in percentage of CO to the jejunum, colon, peritumor muscle, hindlimb, and forelimb muscles were not significant. Reduction in blood flow in large tumors (greater than 0.6 g) was proportional to the reduction in CO, and in small tumors (less than 0.6 g) was more than the reduction in CO. These results suggest that the reduction in blood flow due to hyperglycemia in large tumors is primarily due to reduction in CO and in small tumors due to both systemic and local effect; and changes in the blood flow to normal tissues should not be disregarded when using hyperglycemia in combination with hyperthermia and/or chemotherapy for cancer treatment.

Litomosoides carinii in rodents: immunomodulation in potentiating action of diethylcarbamazine

Abstract: The antifilarial activity of combination of diethylcarbamazine (DEC) and an immunomodulator, N-Palmitoylmuramyl-L-alanyl-D-isoglutamine (NP-MDP) was evaluated against Litomosoides carinii in cotton rat (Sigmodon hispidus) and Mastomys natalensis. DEC was used at 6 mg/kg in cotton rat whereas it was 75 mg/kg x 5 days in mastomys. The immunomodulator was administered at 62.5 to 500 micrograms/animal x 2 days. Combination therapy with optimum dose of immunomodulator resulted in prolonged and significant suppression of microfilaraemia in comparison to infected animals treated only with DEC. The effective doses of immunomodulator alone or in combination with DEC also caused enhanced antibody titre in treated animals. Though combination therapy resulted in prolonged suppression of microfilaraemia, the effect disappeared slowly and caused no damage to adult worms.

Rapid, Multistep Rearrangements of Hydrocarbon Triplet Biradicals at 4 K. A Possible Example of Hot Molecule Effects in Frozen Organic Solvents.

Abstract: La photolyse de diaza-2,3bicyclo [2.2.1] heptenes-2 avec des groupes spirocyclopropyl en position 7 donne des diradicaux alkylidene-2 cyclopentanediyles-1,3